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作者：Yashpal S. Kanwar,, Jun Wada, Sun Lin, Farhad R. Danesh, Sumant S. Chugh, Qiwei Yang, Tushar Banerjee, and Jon W. Lomasney作者单位：Departments of 2 Pathology and 1 Medicine, Northwestern University Medical School, Chicago, Illinois 60611; and 3 Department of Medicine, Okayama University Medical School, Okayama 700-000 Japan

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      【摘要】
   One of the hallmarks of mammalian nephrogenesis includes a mesenchymal-epithelial transition that is accomplished by intercalation of the ureteric bud, an epithelium-lined tubelike structure, into an undifferentiated mesenchyme, and the latter then undergoes an inductive transformation and differentiates into an epithelial phenotype. At the same time, the differentiating mesenchyme reciprocates by inducing branching morphogenesis of the ureteric bud, which forms a treelike structure with dichotomous iterations. These reciprocal inductive interactions lead to the development of a functioning nephron unit made up of a glomerulus and proximal and distal tubules. The inductive interactions and differentiation events are modulated by a number of transcription factors, protooncogenes, and growth factors and their receptors, which regulate the expression of target morphogenetic modulators including the ECM, integrin receptors, and cell adhesion molecules. These target macromolecules exhibit spatiotemporal and stage-specific developmental regulation in the metanephros. The ECM molecules expressed at the epithelial-mesenchymal interface are perhaps the most relevant and conducive to the paracrine-juxtacrine interactions in a scenario where the ligand is expressed in the mesenchyme while the receptor is located in the ureteric bud epithelium or vice versa. In addition, expression of the target ECM macromolecules is regulated by matrix metalloproteinases and their inhibitors to generate a concentration gradient at the interface to further propel epithelial-mesenchymal interactions so that nephrogenesis can proceed seamlessly. In this review, we discuss and update our current understanding of the role of the ECM and related macromolecules with respect to metanephric development. $ n: G, Q! D2 _  S  U4 B/ q( m. A
      【关键词】 renal development integrins metalloproteinases# k) E9 l6 ^- T( @9 r; X& Z
   ORGANOGENESIS DURING EMBRYONIC development constitutes a series of intricate processes that include differentiation and proliferation of pluripotent cells, leading to the formation of a defined, sculpted tissue mass, which is followed by a continuum of cell replication and terminal differentiation in most mammalian organs, with few exceptions, e.g., nervous system. There are certain generalities that are applicable to these processes in the formation of various organs. Usually, the development of a given organ system is accomplished in certain sequential steps, starting with the formation of an anlage, followed by invagination of the primary bud with reiteration into various branches, and, ultimately, differentiation into specific proximal and distal structures. The regulation of these processes involves the participation of various DNA binding proteins, i.e., transcription factors ( 91 ), growth factor hormones and their receptors ( 2 ), and protooncogenes acting as growth factor receptors ( 80 ). They in turn modulate the biology of ECM glycoproteins ( 107 ), ECM receptors, i.e., integrins ( 69 ), cell adhesion molecules (CAMs) ( 132 ), intracellular cytoskeletal proteins ( 88 ), and ECM-degrading enzymes and their inhibitors ( 82 ). Interestingly, in recent years many other molecules, e.g., vitamin A and its metabolites (for instance, retinoic acid and its receptors) ( 50 ), have been shown to influence embryonic development by modulating the transcription of a wide variety of genes, including the Hox family of genes that regulates patterning and posterior body axis development and have been proposed to be involved in epithelial-mesenchymal interactions ( 16, 50 ). Thus the list of embryonic modulators keeps increasing, and, expectedly, the activities of such a diverse group of macromolecules in fetal development are intertwined. For instance, ECM glycoproteins influence intracellular events via their receptors, i.e., integrins, and, thereby, cell differentiation, migration, and polarization. On the other hand, the transcription, translation, and posttranslational modification of ECM macromolecules that interact with integrins have been shown to be regulated by various growth factors or hormones and their receptors. Another set of macromolecules, i.e., CAMs and cadherins, which influence intercellular adhesion and cell-cell (homotypic or heterotypic) interactions and polarization of epithelia, are also important participants in the morphogenesis of various organs during cell-matrix interactions ( 16 ). Finally, critical to cell behavior during differentiation associated with organogenesis is the fundamental process of phosphorylation of various integrins and hormone or growth factor receptors that contain tyrosine or serine/threonine kinase intracellular catalytic domains ( 154, 167 ), whose catalytic activities are known to modulate the expression of various ECM proteins.
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With the complexity of diverse groups of molecules participating in embryonic development taken into account, it seems that one of the essential predetermining factors would be the expression of a given molecule(s) at a particular stage of development of an organ system. This would mean that the macromolecules with restricted spatiotemporal genotypic or phenotypic expressions are relevant only to the morphogenesis of a particular organ system. Thus a morphogen may be defined as a molecule that expresses its concentration gradient in a given tissue and alters the fate of target cells in a dose-dependent manner. The concentration gradients of these macromolecules could also vary in various regions of the same developing tissue, and this would transduce a distinct set of specific cellular events, thereby adding further complexity to the differentiation processes that ultimately lead to regional specialization within an organ system. Moreover, the degree of expression of various morphogens during embryonic life would suggest that their function is specific for a given stage of a developing organ system. Although their expression may be stage and tissue specific, well-orchestrated coordination among the various other macromolecules, expressed during the same time frame, is crucial for morphogenesis to proceed successfully so that a particular visceral organ system can be sculpted with defined biological functions.

In recent years, a large body of literature has become available defining the role of various morphogenetic modulators. Much of the information has been derived from in vivo knockout experiments in mice as well as in vitro, whereby an isolated organ system, i.e., mammary ( 68 ), prostate ( 28 ), salivary glands ( 12 ), lung ( 178 ), and kidney ( 39, 153 ), has been subjected to various experimental manipulations under defined culture conditions. Interestingly, in the morphogenesis of all these organ systems, epithelial-mesenchymal or ligand-receptor interactions seem to be a common feature. Although morphogenesis of the metanephros represents a prototypical example of such interactions, certain unique features are distinctive in renal development in mammals ( 39, 153 ).

OVERVIEW OF THE DEVELOPMENT OF THE MAMMALIAN METANEPHROS
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Mammalian nephrogenesis commences with the successive appearance of the pronephros, mesonephros, and metanephros as a craniocaudal wave of cellular differentiation in the nephrogenic cord lying alongside the nephric or Wolffian duct ( 153 ). The pronephros is functional to a large extent in lower vertebrates only, e.g., fish, and the mesonephros is fully operational in amphibians. In mammals, the pronephros and mesonephros are vestiges of the nephrogenic cord, and their appearance is transitory; it is the metanephros that matures to form a functional multiunit organ system, i.e., the kidney. Metanephrogenesis commences at days 10-11 in the mouse and at about week 5 of gestation in humans ( 153 ). During this process, an epithelium-lined tubular structure arising from the Wolffian duct, i.e., the ureteric bud, interacts with a loosely organized mesenchymal mass, i.e., the blastema, located on the lateral aspect of the aorta in the most caudal segment of the nephrogenic cord. This epithelial-mesenchymal interaction leads to a dramatic transformation of the mesenchyme into an epithelial phenotype, which reciprocates by inducing the ureteric bud to undergo arborization and generation of nascent nephrons. It is of interest that mesenchymal differentiation continues even after the removal of the inducer, i.e., the ureteric bud, and differentiation can be maintained by soluble factors such as embryonic extracts ( 10, 53 ). On the other hand, soluble factors/molecules, e.g., anti-GD3 antibodies, can interfere with the inductive interaction even if the mesenchyme and the ureteric bud are in close contact with one another ( 151 ). Along these lines, it is conceivable that the soluble factors released by the mesenchyme could influence the branching morphogenesis of the ureteric bud in in vitro systems ( 145 ). Nevertheless, epithelial-mesenchymal interaction(s) is still an accepted biological precept for in vivo renal development, based on which nascent nephrons are formed by undergoing the following developmental stages: condensate/vesicle, comma-shaped body, S-shaped body, and precapillary body ( 153 ). The precapillary bodies, on vascularization by the processes of vasculogenesis (in situ blood vessel formation) and angiogenesis (sprouting of preexisting capillaries), form the functioning mature glomeruli of the kidney ( 36, 136, 153 ), and these processes are modulated by various growth factors and their receptors and are described in recent reviews by Abrahamson and Gomez and their colleagues ( 52, 136 ).7 d2 x5 S# n' g5 y+ o8 m' j

For the precise delineation of various events governing metanephric development, several in vitro techniques, including organ or cell culture systems, have been successfully employed. For instance, Madin-Darby canine kidney (MDCK) cell culture has been useful in studying the branching morphogenesis of tubules and development of their epithelial junctions and polarity characteristics ( 121 ). In addition, the recent use of the three-dimensional Matrigel cell culture system has yielded deep insights into various processes that regulate tubulogenesis and the role of various growth factors and matrix-degrading enzymes in in vitro development of the mammalian metanephros ( 145, 164 ). Despite recent advances in culture techniques, the age-old in vitro metanephric organ culture transfilter technique established by Grobstein ( 56 - 58 ) is still in use and has substantive value in the study of the morphogenesis of the whole kidney, the glomerulus, and the tubules. In this culture system, various developmental stages, with the exception of vascularization of the metanephros, can be studied. The technique employs harvesting either uninduced ( day 10.5 ) or induced ( day 11.5 ) mouse metanephric mesenchyme, placing it on a microporous ( 0.8 µm) filter, and maintaining it in culture for 7-10 days. Uninduced mesenchyme can be induced by gluing the ureteric bud or a heterologous inducer, e.g., embryonic neural tissue, to the bottom of the filter. In doing so, the metanephric mesenchyme receives inductive signals from the ureteric bud through the pores of the filter, perhaps by the establishment of transfilter pseudopodial cell-cell contacts ( 153 ) or from the ingrowth of neuronal processes in the case of the heterologous inducer ( 152 ), although induction by soluble factors is also conceivable ( 78, 129 ). The induced mesenchyme then differentiates, leading to the formation of glomerular and tubular elements, while a part of it develops into stroma or interstitium of the kidney. These in vitro organ culture experiments emphasize that the inductive neotransformation of the mesenchyme is to a large extent modulated by the molecules expressed at the epithelial-mesenchymal interface or ligands expressed in the mesenchyme and receptors in the ureteric bud epithelium that exert paracrine-juxtacrine interactions ( Fig. 1 ).

Fig. 1. Schematic drawing depicting the paradigm of reciprocal induction of mesenchymal cells and ureteric bud epithelia in embryonic kidney. The receptors of growth factors (GFs) and of ECM, i.e., integrins, are localized in the epithelial cells of the ureteric bud. The protooncogenes, such as c-ret and c-ros, which function as tyrosine kinase receptors, are localized in the ureteric bud epithelium. Although the ligands of many protooncogenes are unknown, the ligand of c-ret is a glial-derived neurotrophic factor and is shown here to be expressed in the metanephric mesenchyme. Among the ECM proteins, some are expressed in the mesenchyme, whereas others are expressed at the epithelial-mesenchymal interface. It should be noted that at times receptors may be expressed in the mesenchyme, whereas ligands are expressed in the ureteric bud epithelium.
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The concept of such epithelial-mesenchymal/juxtacrineparacrine interactions in nephrogenesis was originally described for ECM proteins and their receptors ( 58 ). Current data suggest that these interactions are applicable to other macromolecules, including transcription factors, protoonocogenes acting as tyrosine kinase receptors, and growth factors and their receptors ( 71, 142 ). In the context of such interactions, these diverse sets of molecules exhibit a fair degree of interdependence in the regulation of growth and development of the kidney. The interdependence of growth factors and ECM proteins is reflected by the fact that the latter may act as storage depots for certain growth factors or may contain growth factor-like domains ( 142 ). In such a scenario, the ECM would be expected to modulate the biological activities of various growth factors, e.g., transforming growth factor (TGF)-, whereas TGF- in turn regulates the synthesis of ECM proteins ( 160 ). Similarly, c-ret, a protooncogene that regulates nephrogenesis ( 156 ) and ECM expression in metanephric tissues ( 100 ), serves as a receptor for glial-derived nerve growth factor (GDNF) ( 165 ), the latter apparently structurally related to members of the TGF- superfamily and playing a vital role in embryonic organ development ( 113, 131, 148 ). Thus the actions of this group of diverse molecules are intricately linked, and this review addresses the role of various ECM proteins, their receptors, and the molecules relevant to ECM biology.  y4 N) X0 N, t

GENERAL DISCUSSION OF ECM, ECM-DEGRADING ENZYMES, INTEGRINS, AND CAMS
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The role of ECM in metanephric development was conceptualized by the pioneering work of Grobstein and Saxen almost four decades ago ( 57, 58, 153 ). They postulated that the basement membrane (BM) of the ECM, interposed between the leading edge of the ureteric bud and the blastema, has a "paracrine" effect in facilitating the interactions among the two cell types that lead to conversion of the metanephric mesenchyme to an epithelial phenotype. The BM glycoproteins are constitutively expressed and are the cytosecretory products of the native epithelium, as in salivary and breast glands ( 9, 68 ), or mesenchyme-derived epithelium, as in the metanephros ( 57, 153 ). Because the mesenchyme also induces epithelial branching morphogenesis and de novo synthesis of matrix molecules at the same time, it can be currently perceived as having a self-stimulatory or "autocrine"(?) effect on embryonic tissues during development. Such unique functional properties of ECM proteins were originally proposed on the basis of their expression in fetal tissues. However, in view of current knowledge, it can be argued that the expression of a given macromolecule in a particular tissue does not necessarily imply its direct relevance to a specific stage of embryonic development. Moreover, sometimes even in the face of their in vivo gene disruption, nephrogenesis proceeds normally. This may be related to redundancy in gene functions or compensation for functions by other genes. Also, the functions of some of the constitutively expressed genes/proteins remain elusive in vivo, whereas their role in metanephrogenesis can be readily demonstrated in the transfilter organ culture system ( 6, 14, 57, 153 ). Nevertheless, numerous investigators have conclusively demonstrated the morphogenetic role of some of the ECM and ECM-related macromolecules in renal development, both in vivo and in vitro, and it may be worth stressing here again that the impetus for these studies evolved after the initial detection of a given stage-specific, constitutively expressed glycoprotein in metanephric tissues.
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ECM PROTEINS
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A large number of ECM proteins are expressed during renal development ( Table 1 ). Although they are constitutively expressed but their expression is largely modulated by the growth factors and their receptors, the latter are endowed at times with tyrosine kinase catalytic domains and belong to the family of protooncogenes. The ECM proteins expressed in the metanephric mesenchyme include interstitial collagens, tenascin, nidogen (entactin), fibrillins, osteopontin, and fibronectin; those associated with the BM include type IV collagen, laminin, proteoglycans (PGs), nephronectin, and tubulointerstitial antigen (TIN-Ag) ( 42, 71, 108, 109 ). The expression of these ECM proteins, especially mesenchymal proteins, is asynchronous. For instance, interstitial collagens disappear by day 11 after induction, whereas the gene expression of splice variants of fibronectin, i.e., EIIIA, EIIIB, and V, decreases rapidly after day 15 / 16 of murine gestation ( 126 ). Although mesenchymal proteins are expressed in the metanephros, their role is somewhat enigmatic. For instance, anti-fibronectin antibodies are incapable of perturbing the conversion of the mesenchyme to polarized epithelium. Although arginine-glycine-aspartic acid-serine peptides, which bind to the fibronectin receptor, do reduce lobulations of embryonic lungs ( 36 ), they are ineffective in inhibiting in vitro nephrogenesis ( 151 ). Also, no nephric defects in mice lacking fibronectin have been described ( 49 ). Tenascin is another mesenchymal protein that interacts with fibronectin and PGs, and it appears transiently around the nascent nephron. Its expression decreases with the inhibition of tubulogenesis, however, and no renal abnormalities are detected on tenascin gene disruption in mice ( 5, 144 ). Nidogen is a mesenchymal factor that allegedly seems to have a role in renal organogenesis. It is produced by mesenchymal cells and interacts with the 1 -chain of laminin-1 ( Fig. 2 ). This interaction is apparently crucial for the assemblage of the BM ( 41 ). Interestingly, disruption of the binding of the laminin-1 1 -chain to nidogen by a blocking antibody leads to inhibition of nephrogenesis in embryonic renal explants in culture ( 40 ). Similarly, ablation of nidogen binding to the 56-amino acid module in laminin-1 1 displays bilateral renal agenesis in a majority of mouse fetuses ( 181 ). However, it should be noted that gene inactivation of nidogen-1 by itself does not result in any obvious phenotype or abnormalities in renal development ( 117 ). It is conceivable that other isoforms, i.e., nidogen-2, may compensate for its functions ( 112 ). Other mesenchyme-derived proteins whose functions can be ascribed in vitro include fibrillin-1 and osteopontin. Fibrillin-1 interacts with v 3 -integrins expressed in the ureteric bud epithelium. Inclusion of fibrillin-1 antisense oligo in metanephric culture has been shown to induce dysmorphogenesis of the kidney ( 76 ). Osteopontin is a secreted phosphoprotein that interacts with CD44, a cell-surface proteoglycan hyaluronic acid receptor, and v 3 - and 8 1 -integrin. Treatment of metanephric explants with anti-osteopontin blocking antibodies has been shown to induce their dysmorphogenesis ( 137 ). In contrast to the limited functional data on mesenchymal proteins, the role of integral BM glycoproteins, e.g., laminin, PGs, and TIN-Ag and their receptors, is more well defined in embryonic development ( 74, 89, 93, 110 ). Type IV collagen exhibits restricted spatiotemporal distribution in the fetal metanephros; however, various gene deletion and insertional mutation studies suggest no definitive role during embryonic development. Nevertheless, mice with gene deletion of 3 (IV) ( 26, 111 ) or mutation in 3 (IV)- and 4 (IV)-chains ( 102 ) develop an interesting phenotype at 3-4 wk after birth. They develop uremia, proteinuria, and glomerular BM (GBM) changes that are reminiscent of those seen in Alport syndrome. Last, although a majority of the integral BM proteins are expressed around the nephron progenitors, i.e., condensate, S-shaped bodies, and glomerular capillaries, and around the tubules ( 38 ), the expression of their individual polypeptide chains varies and even though exhibits stage-specific spatiotemporal distribution.* z8 d" {! {% I. R5 M- h
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Table 1. Spatiotemporal expression of ECM proteins during metanephric development# q" p1 M4 T) k4 T) {
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Fig. 2. Schematic model depicting interactions between the various chains of laminin-1, integrin 6 1, - and -dystroglycan subunits, and mesenchymal cell-derived nidogen (entactin) during epithelial morphogenesis. Conceivably, integrins, such as 6 1 and -dystroglycan, along with sarcospan (Sp) and sarcoglycans (SGs) are involved in various transductional events that may be relevant in cell-matrix interactions influencing the organogenesis of the mammalian kidney. Arrowhead with N represents the N-linked oligosaccharide chains attached to the various components of the dystroglycan complex. Both integrins and dystroglycan bind to the cytoskeletal elements of the cell directly or indirectly via various linking proteins.

Laminins

An extensive amount of work carried out over the past two decades suggests a pivotal role of various forms of laminins, e.g., laminin-1, -5, and 5 -chain, in development. A typical laminin is made up of -, -, and -subunits assembled into a cross-shaped structure. About 15 heterodimeric forms of laminins, made up of 5 -, 4 -, and 3 -subunits in various combinations, have been described ( 41, 127 ), and they are involved in a variety of biological processes, including cell adhesion, growth, and differentiation, by interacting with cellular receptors. These biological processes are in large part modulated by the interaction of a globular domain in the COOH terminus of the -chain with other receptors. The G domain contains five repeating modules, known as LG1-LG5. The LG1-LG3 modules are connected to LG4-LG5 by a linker domain. Laminin-1 is a high-molecular-weight protein made up of 1 -, 1 -, and 1 -chains, and it is believed to participate in metanephric development, especially during the polarization of the epithelia ( 36 ). The expression of laminin chains is asynchronous during early development and is also species and stage specific ( 36 ). The mRNA expression of 1 and 1 laminin chains is both seen in the nephric mesenchyme and detectable in vitro 24 h after the induction of nephrogenesis in mice. Although expression of the 1 -chain appears after 2 days, coinciding with the appearance of polarized epithelia in the comma- and S-shaped bodies, its expression is gradually lost from the ureter, distal tubules, and GBM and becomes confined to the mesangium along with the laminin-2 ( 1 1 1 ) isotype in mature animals. Ekblom ( 36 ) demonstrated the role of laminin in nephrogenesis in an vitro culture system by using elastase-generated peptides and chain-specific antibodies, i.e., against the COOH ends of 1 (E3, LG4-LG5 modules) and 1 1 1 (E8, LG1-LG3 modules); the NH 2 terminus of 1 -chains (E4); and the central region of the whole laminin molecule containing the YIGSR-dependent laminin receptor binding sites ( Fig. 2 ). Similarly, the antibodies against E3, the heparin binding domain and more recently found to bind to the dystroglycan complex (see ECM RECEPTORS, INTEGRINS, AND BINDING PROTEINS ), and E8, the 6 1 -integrin receptor binding site ( 159 ), were shown to inhibit the morphogenesis and formation of polarized epithelium ( Fig. 2 ), whereas antibodies against the central region of the laminin molecule were incapable of perturbing renal development ( 36 ). During development, other roles of laminin include angiogenesis and integrin receptor-mediated attachment, with the activities confined to YIGSR sequences of laminin- 1 and RGD sequences of the 1 -chain, respectively ( 41 ). In early nephron progenitors, i.e., the S-shaped body, laminin-1 ( 1 1 1 ) is seen in the vascular cleft, whereas in the intermediate capillary loop stage the expression switches to laminin-11 ( 5 2 1 ) ( 1 ). The expression of the 1 -chain is confined to larger blood vessels ( 36 ), whereas that of the 2 -chain is confined to capillaries of mature renal glomeruli. Such stage-specific isoforms or switch in their expression are also seen in other ECM proteins, type IV collagen chains, and PGs.

Among the other family members, the role of laminin-5 ( 3 3 1 ) has been recently demonstrated in vitro. Laminin-5 most likely exerts its effect via 3 1 - and/or 6 4 -integrin receptors ( 186 ). Addition of anti-laminin-5 blocking antibody to the culture medium perturbs the organogenesis of the embryonic kidney ( 186 ). Of great interest is the biology of a recently discovered novel 5 -chain which is a component of laminin-10 ( 5 1 1 ) and -11 ( 5 2 1 ). The mice deficient in 5 usually die late in embryogenesis with no obvious renal phenotype. However, a minority of them lacked one or both kidneys ( 110 ). On closer inspection, glomerular development was found to be aberrant in that the mutant mice had constricting glomeruli with a disarray of podocytes and defective assemblage of GBMs. In addition to a deficiency in the 5 -chain, its novel receptor, i.e., Lutheran blood group glycoprotein, was also lacking in mutant mice ( 115 ). The abnormalities in GBMs were attributed to an absence of laminin-11 in the 5 mutant mice, thus implying that the switch from the 1 -chain of laminin-1 to the 2 -chain of laminin-11 also plays a role in the macromolecular assemblage of GBMs. This notion is strengthened by the observations made in mutant mice lacking s-laminin/laminin- 2, which display heavy proteinuria although the GBMs appear ultrastructurally normal ( 122 ). Also, these mice do not reveal any molecular abnormalities in collagenous or noncollagenous components, which may suggest that the 1 -chain compensates for the functions of 2, thus yielding normal morphology of the GBMs.# [, }: c% V% z
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Several species of PGs have been described because of the original description of heparan sulfate (HS) as the integral constituent of renal BM or mesangial matrices ( 72, 73 ). They include perlecan, i.e., HS-PG, chrondroitin sulfate PG (CSPG), decorin, biglycans, agrin, leprecan, and type XVIII collagen ( 42 ). The latter is a nonfibrillar collagen belonging to the subfamily of multiplexins and has sulfated disaccharide chains attached to its polypeptide as in HS-PG ( 46 ). In addition, there are certain cell surface-associated PGs expressed in the kidney, including glypicans and syndecans ( 13, 54 ). Many of the PGs are believed to play a significant role in various developmental processes in several tissues ( 180 ). The classic PGs are made up of glycosaminoglycan (GAGs) chains that are bound by O -glycosidic linkage to the core peptide. Initially, at the time of induction, the sulfated PGs are highly concentrated at the "tips" of the ureteric bud branches, the epithelial-mesenchymal interface and the site where nascent nephrons are formed. Later, they are seen around the condensate and persist in the BMs throughout the fetal and neonatal periods ( 93 ). Inhibition of the synthesis of sulfated PGs by puromycin or the addition of GAG chains onto the core peptide is associated with blunting of the tips of the ureteric bud branches and dysmorphogenesis of the kidney ( 93, 96 ). Incidentally, the addition of heparin sulfate, and not HS, to the culture medium also inhibits nephrogenesis ( 133 ). Thus it appears that the biological actions of PGs are mediated via their GAG chains, and this notion has been supported by experiments with salivary glands in which enzymatic deletion of GAGs was shown to inhibit lobulogenesis ( 9 ). The GAG chains can interact with other matrix molecules, such as the E8 fragment of laminin ( 159 ), and they also act as reservoirs for various growth factors, e.g., basic FGF ( 142 ), and thus can influence morphogenesis by more than one mechanism. Also, the enzymes responsible for the sulfation of GAGs, e.g., HS-2-sulfotransferase (HS2ST), play a major role in modulating the effect of PGs on renal development. HS2ST is required for mesenchymal condensation around the ureteric bud and in the initiation of branching morphogenesis, and gene deletion of HS2ST results in bilateral agenesis ( 19 ). Interestingly, the perlecan null mice do not reveal any defective renal phenotype, but most of them die at midgestation due to bleeding diathesis ( 123 ). Those that survive appear to have normal BMs. Type XVIII collagen null mice do not appear have any renal abnormal phenotype, although ocular and vascular abnormalities are observed ( 46 ). These may be related to the dysfunction of the endostatin domain of type XVIII collagen. The latter interestingly has been shown to modulate branching morphogenesis of the ureteric bud in vitro ( 79 ).! Y' b- z( ^: |

Among the cell-surface PGs, the syndecans are more or less receptor forms of transmembrane HS-PGs. They are present in the mesenchyme and early differentiating epithelium, they gradually disappear with the maturation of the nephron ( 13 ), and no distinct role in renal organogenesis has been described in the literature. The glypicans (Gpcs) are HS-PGs that are linked to the cell surface via a glycosyl-phosphotidylinositol anchor and are composed of six family members ( 55 ). Gpc3 is expressed in the kidney, and its deficiency leads to enhanced ureteric bud branching, cortical collecting duct hyperplasia with reduced growth and apoptosis in medullary collecting duct cells, ultimately resulting in dysplastic kidneys, reminiscent of the phenotype observed in patients with Simpson-Golabi-Behmel syndrome ( 55 ). Along these lines, endostatin, a protein that binds to Gpc, has been shown to regulate branching morphogenesis of the ureteric bud in vitro ( 79 ). Interestingly, Gpc3 modulates bone morphogenetic protein (BMP)and FGF-mediated effects during renal branching morphogenesis ( 54 ), suggesting that the biology of PGs and growth factors is interlinked. A brief exemplary discussion of this intricate relationship is given below.

A number of growth factors and their receptors have been shown to modulate the expression of PGs and thus are belived to regulate morphogensis of the kidney. They include insulin, IGF-I, and TGF- and - ( 97 - 99, 138 - 140, 176 ). Analogous to ECM ligand-integrin receptor interactions, epithelial-mesenchymal interactions are also amenable to growth factors and their receptors. For instance, ligands like insulin or IGF-I are expressed in the mesenchyme, whereas their receptors are in the ureteric bud epithelia, and both of them display restricted spatiotemporal distribution during metanephric development ( 97, 99, 176 ). The evidence for the linkage between growth factors and ECM proteins in renal development is derived from in vitro studies, in which the addition of IGF-I or insulin to the organ culture medium was found to result in a hypertrophic/hyperplastic response in metanephric explants, with parallel increased mRNA and protein expression of PGs ( 97, 98 ). Furthermore, in vitro experiments revealed that gene disruption of IGF-I or insulin receptors by addition of antisense oligonucleotides to the organ culture leads to atrophy of the explants, with markedly decreased expression of PGs, especially at the tips of ureteric bud branches, the site where epithelial-mesenchymal interactions take place ( 97, 176 ). Similarly, gene disruption of the GDNF receptor, i.e., c-ret protooncogene with a phosphotyrosine kinase catalytic domain ( 165 ), leads to a remarkable dysmorphogenesis of the kidney concomitant with a dramatic decrease in the expression of ECM proteins, in particular that of PGs ( 100 ). Conceivably, GDNF, a molecule related to the TGF- superfamily, is expressed in the mesenchyme, whereas c-ret is in the ureteric bud epithelia, and in vivo gene disruption of either of them also leads to agenesis or hypogenesis of the kidney ( 148, 156 ).2 D5 A5 R! P/ G9 Y$ B2 y0 L0 i
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Another member of the TGF- superfamily that seems to play a role in renal development is BMP-7. BMP-7 is involved in the mineralization of cartilage ( 66 ). Its spatiotemporal mRNA expression in the metanephros is unclear because in certain reports its mRNA expression at day 14.5 of gestation is indicated in the mesenchyme of the nephrogenic zone, the condensing aggregate, and the epithelia of comma- and S-shaped bodies ( 33 ), whereas other reports indicate its expression in both the ureteric bud and condensed mesenchymal cells around them besides the condensing aggregate, comma- and S-shaped bodies, and vascularized glomeruli ( 103, 171 ). These differences may be related to different antisense constructs used for in situ hybridization. Nevertheless, two independent studies indicate that BMP-7-deficient mice exhibit marked hypogenesis/agenesis of the kidney in metanephric development ( 33, 103 ). Whether a deficiency in BMP-7 leads to altered expression of PGs, which then results in aberrant metanephric development, remains to be investigated. Further evidence that TGF-, a modulator of PG expression, plays a role in nephrogenesis is derived from cell culture studies, where it was found to perturb tubulogenesis of MDCK cells grown in collagen gels ( 149 ). The mechanism as to how TGF- modulates the expression of PGs is rather complex. TGF- seems to exert its influence via approximately nine binding proteins or receptors, and among them the first three are well characterized ( 8, 17 ). Type I and II receptors contain serine/threonine kinase domains. Subsequent to their heterodimerization, there is activation of the Mad (for Mothers against dpp) signaling pathway, leading to targeted gene expression. Type III receptors are made up of endoglin and betaglycan, and both are transmembrane PGs with serine and threonine residues likely to be phosphorylated by protein kinase C, which would be expected to influence the expression of the target genes. Other BMPs that play a role include BMP-2 and -4, because they are also expressed in the embryonic metanephros. The addition of BMP-4 to the culture medium is found to inhibit ureteric bud branching; however, notable renal abnormalities are observed in BMP-4 heterozygous null mutants ( 105, 106 )./ I3 a) K& b$ A$ g( l5 H+ G  c

ECM RECEPTORS, INTEGRINS, AND BINDING PROTEINS
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Of the known molecules that are expressed at the epithelial-mesenchymal or cell-matrix interface are the well-studied molecules known as integrins. Integrins are heterodimeric, noncovalently bound transmembrane glycoproteins and are made up of - and -chains. They are ubiquitously distributed and mediate diverse biological functions, including cell-cell and cell-matrix interactions, cell polarity, cell migration, and angiogenesis ( 30, 69 ). In the event there is disruption in cell-matrix interactions, the mesenchyme is likely to undergo apoptosis as observed in high-glucose ambience ( 75 ). To date, about 20 integrins have been discovered in various tissues, and they serve as receptors for a number of morphogenetic ECM proteins, including laminins, collagens, fibronectin, osteopontin, nephronectin, vitonectin, and tenascin ( Table 2 ). Their interaction with ECM proteins is Ca 2  dependent and peptide sequence specific, and substrate specificity is largely determined by the -subunit. The intracytoplasmic tail of the -chain is responsible for its interactions with the cell cytoskeleton via binding to talin, vinculin, and -actinin and may be also involved in transductional events, whereby -subunits undergo tyrosine phosphorylation ( 30, 69 ). Like ECM proteins, integrins exhibit spatiotemporal expression in the mammalian metanephros ( 86 ). The -subunit seems to have a wider distribution, whereas expression of the -subunit is much more restricted. The 1 1 -and 4 1 -integrins are widely distributed in the uninduced mesenchyme. Like its ligand fibronectin, 1 1 disappears after induction. Expression of 3 1, 2 1, and 6 1 is at the interface between the basal lamina abutting the base of the foot processes of developing podocytes, endothelia, and tubular epithelium, respectively ( 83, 84 ). The 6 -subunit, expressed in the cells of the condensing mesenchyme and polarized tubular epithelium, codistributes with the laminin 1 -chain. 6 1 -Integrin serves as a receptor for the E8 fragment of the 1 -, 1 -, and 1 -chains of laminin, and like the E8 laminin-1 fragment, anti- 6 antibodies also perturb the formation of polarized nephric epithelium and perturb tubulogenesis of the metanephros in vitro ( 36, 44, 186 ). Besides 6 1, 2 1 and 3 1 also bind to laminins, and 2 -integrin is expressed in the distal tubules and 3 in the maturing glomerular podocytes ( 37 ). Although 2 1 binds to laminin, its affinity for type IV collagen is higher ( 130, 168 ). Because type IV collagen is present during the early stages of tubule formation and maturation of nephrons, it is likely that its interaction with 2 1 may be relevant to renal tubulogenesis.2 o/ |1 |$ }( A0 t
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Table 2. ECM proteins and their binding proteins/integrin receptors expressed during metanephric development8 X1 ?" |9 d/ V+ y/ V3 m+ f
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The notion that integrins play a role in metanephric development is also supported by in vitro organ culture and in vivo knockout experiments. For instance, inclusion of anti- 3 or - 1, a receptor for laminin-10 and -11 causes inhibition of ureteric bud branching morphogenesis, whereas concomitant treatment with anti- 3 and - 6 induces a marked reduction in the size of the metanephros ( 186 ). It needs to be emphasized that 3 and 6 form heterodimers such as 3 1 - and 6 4 -integrins and share a common ligand, laminin-5; exposure of their blocking antibodies leads to aberrant metanephrogenesis (see above). Along these lines, in vitro gene disruption of 2 1 -integrin has been shown to induce a failure in branching morphogenesis of tubules in the MDCK cell collagen gel culture system ( 143 ). Because the E8 fragment of laminin-1 also interacts with 3 1 - and 7 1 -integrins, this would suggest that their common -subunit may also have a functional role in morphogenesis ( 83 ). The role of 1 in nephrogenesis has received limited attention ( 44 ), but its in vivo gene disruption is associated with peri-implantation lethality ( 161 ). Further support for its role in organogenesis is also derived from other in vitro model systems; i.e., anti- 1 antibodies have been shown to cause functional impairment in mammary epithelia and block the differentiation of colon carcinoma cells and the formation of glandular structures in three-dimensional collagen gels ( 36 ). Among the v -related integrins, v 3 has been reported to be present on the endothelial cells of glomerular and extraglomerular capillaries ( 83 ). v 3 Is a promiscuous integrin receptor and binds to a number of ligands, including vitronectin, fibrinogen, von Willebrand factor, thrombospondin, fibronectin, osteopontin, bone sialoprotein, thrombin, laminin, and collagen type I and IV ( 51 ). In view of such a wide range of interactions, v 3 would be expected to participate in diverse biological functions. Its role in angiogenesis has been well defined. Also, v -related integrins have been shown to play a role in metanephric development, as assessed by in vitro gene disruption experiments ( 174 ). Interestingly, in vitro treatment of anti- v 3 results in inhibited growth of the metanephros like that seen with the antibodies to its ligand osteopontin, with accentuated apoptosis of the mesenchyme ( 137 ).$ b) b- ^& C) y& D
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Osteopontin, as indicated earlier, is a ligand for 8 1 -integrin, and the most convincing role of integrins in metanephric development is attested to by knockout experiments ( 32, 116 ). The other known ligands of 8 1 include fibronectin, vitronectin, tenascin C, and preosteoblast epidermal growth factor-like repeat protein with meprin. The latter is expressed in the kidney and may play a role in metanephric development ( 114 ). Expression of 8 1 occurs in the induced metanephric mesenchyme during the time frame when growing tips of the ureteric bud intercalate into the mesenchyme to exert epithelial-mesenchymal interactions. Another recently described ligand for 8 1 is nephronectin, an ECM protein with EGF-like repeats, a mucin region containing an RGD sequence, and COOH-terminal MAM domain expressed in the ureteric bud epithelium, thus making it amenable to suitable epithelial-mesenchymal interactions and for renal development to proceed normally ( 18 ). With gene disruption of the 8 -subunit of 8 1 -integrin, severe deficits in nephrogenesis are observed ( 116 ). More than 50% of 8 1 mutants are born without kidneys or ureters, and the remainder show variable renal and ureteric abnormalities. Besides 8 1, results after gene disruption of other integrins are not encouraging. A target mutation in the integrin- 3 gene has been reported to have no abnormal phenotype, although mild growth retardation is observed ( 85 ).

Akin to the integrin receptors is a unique transmembrane protein that also links the ECM glycoproteins to the intracellular filamentous network, and it is referred to as dystroglycan ( 22, 43 ). It is expressed in the embryonic metanephros and seems to be relevant to morphogenesis of the mammalian kidney. Dystroglycan is a receptor for a number of BM proteins, including laminin-1 and -2, perlecan, and agrin ( 22, 43 ). Dystroglycan in its macromolecular complex is made up of several proteins that ultimately mediate transmembrane interactions between ECM proteins and intracellular cytosleletal elements ( 22, 43 ). This complex includes six proteins, i.e., -and -dystroglycans, -, - and -sarcoglycans, and a 25-kDa protein. Data from various investigations collectively indicate that -dystroglycan is extracellular, and it binds to E3-like G domains of laminin-2 in muscle and possibly interacts with laminin-1 as well. Transmembrane -dystroglycan binds to the COOH terminus of intracellular dystrophin/utrophin, and the NH 2 terminus of the latter has binding affinities with F-actin ( 34, 135 ). By in situ hybridization, it has been shown that dystroglycan and laminin 1 -chains are coexpressed in epithelial components of the developing metanephros and both exhibit a restricted spatiotemporal distribution ( 35 ). Because extracellular -dystroglycan interacts with the E3 domain of the laminin 1 -chain that regulates morphogenesis of the kidney, it is possible that the dystroglycan complex plays a role in development ( Fig. 2 ). Indeed, inclusion of monoclonal antibodies, which are known to block the binding of -dystroglycan to laminin-1, in culture perturbs the morphogenesis of the embryonic metanephros, in particular that of the differentiating epithelium ( 35 ). It is interesting to note that dystroglycan, by interacting extracellularly with laminin and mesenchymal factor nidogen and intracellularly with epithelial utrophin or dystrophin and actin, exemplifies classic epithelial-mesenchymal or ligand-receptor interactions and reinforces the observations that are fundamental to the core biological precepts in the developmental biology of the metanephros ( 56 ).

CAMS AND SIALOGLYCOCONJUGATES! r8 G( y. E0 M) r; |- [5 O

Two major families of proteins appear to play a major role in cell adhesion followed by epithelial differentiation and polarization. Like integrin receptors or the dystroglycan complex, some of these CAMs are integral plasma membrane glycoproteins, e.g., E-, N- and P-cadherin, belonging to class I cadherins, and interact with cytosolic proteins, e.g., -, -, and -catenin (plakoglobin), which in turn interact with the actin filament network. Conceivably, such an interaction may exert a substantial influence on metanephric development ( 60 ). For instance, a -catenin-E-cadherin complex may be involved in the increased adhesiveness of cells to form condensates around the ureteric bud branches during the comma- and S-shaped-body stage of metanephric development. The cadherin 80 members, and 16 subtypes of mammalian cadherins have been identified in mice that can be classified under classic cadherins, the latter containing 5 cadherin repeats in their extracellular domain and mediating Ca 2  -dependent cell adhesion ( 185 ). E-cadherin (L-CAM or uvomorulin), a prototype of class I cadherin and a glycosylated protein with adhesive properties confined to its 26-kDa fragment, appears subsequent to induction in the condensates and at lateral surfaces of the differentiated polarized tubular epithelium, coinciding with the expression of the laminin 1 -chain. Initially, E-cadherin is expressed at the tips of the ureteric bud and later in the upper limb of the S-shaped body that is destined to become distal and collecting tubules ( 29 ). N-CAM, a heavily sialyated glycoprotein, is distributed in the uninduced mesenchyme only. The role of both L-CAM and N-CAM is unclear because their antibodies do not inhibit the conversion of the mesenchyme to an epithelial phenotype of the metanephros ( 81, 170 ) or affect the morphogenesis of MDCK cells ( 59 ). Also, N-CAM-deficient mice do not exhibit any overt renal abnormalities ( 27 ). Incidentally, anti-uvomorulin antibodies perturb compaction at the 8-16 cell stage of primitive embryonic tissues, which may be due to interference with protein kinase C-dependent phosphorylation ( 157 ) and disruption of uvomorulin-actin interactions mediated via -and -catenins, which associate with the intracytoplasmic domain of uvomorulin ( 125 ).
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Another CAM, a prototype of class II cadherin, is K-cadherin/cadherins-6. It is expressed in the lower and middle limbs of the S-shaped body, the progenitor of proximal tubules. It mediates Ca 2  -dependent homophilic cell aggregation ( 184 ), and its role in nephrogenesis has been recently well documented in vivo using transgenic approaches ( 104 ). Cadherin-6 seems to modulate events regulating mesenchyme-to-epithelial conversion in the metanephros. Also, anti-cadherin-6 antibodies have been shown to inhibit aggregation of induced mesenchyme in in vitro organ culture systems ( 24 ). Thus it seems that between E-cadherin and cadherin-6 there is a certain degree of parallelism between their expression and relevance to tubulogenesis in the metanephros. Another class I cadherin, R-cadherin, is expressed similarly to cadherins-6, and it may play a role in the transition of epithelialization of the mesenchyme ( 29 ). However, gene disruption of R-cadherin reveals delayed maturation of the kidneys, but the phenotype observed as a result of R-cadherin gene disruption did not reveal overt abnormalities in the genitourinary system, and the degree of phenotypic change is not appreciably different from that observed in cadherin-6-, P-cadherin-, or N-cadherin-deficient mice ( 29 ). Surprisingly, intercrossing of mice between different cadherin-deficient animals also did not result in any notable phenotype as far as genitourinary development was concerned, which again suggests a certain degree of redundancy in terms of functionality among various cadherins ( 29 ). In addition to E-, N-, K-, and R-cadherin, KSP-cadherin, belonging to a subfamily of classic cadherins, is also expressed in the kidney along the entire length of the nephron. Although it is not involved in the directional morphogenesis of the early metanephros, it probably plays a role in the maintenance of the terminal differentiated tubular epithelial phenotype ( 158 ). Tensin is another recently described F-actin binding protein that is expressed in the kidney; however, it only regulates postnatal renal development ( 101 ). Thus it appears that the actin binding proteins, tensin or cadherins/catenins, play some role in metanephric development, and whether they are essential to organogenesis of the embryonic kidney is debatable. Finally, L1 is another recently described CAM, which belongs to the Ig superfamily. It is expressed in the collecting ducts, and exposure of anti-L1 antibodies induces dysmorphogenesis of the ureteric bud, suggesting its potential role in in vitro metanephric development ( 31 ).: r! y  c7 t! E+ o! f( C

Besides classic CAMs, there are several newer molecules that have been described in the literature that regulate cell-cell or cell-matrix interactions and are expressed in the kidney, and thus, conceivably, play a role in renal development. They include sialoconjugates ( 67, 90 ), e.g, podocalyxin ( 155 ), and sialylated glycosphingolipids, e.g., gangliosides ( 151 ), N -linked oligosaccharides ( 45 ), and galectins ( 11, 25 ). Podocalyxin is a major sialoglycoprotein that is expressed in the developing glomerular epithelium and is involved in podocyte-GBM interactions ( 155 ). However, its role in nephrogenesis remains to be established. The gangliosides are widely distributed in various tissues and display cell-cell and cell-substratum adhesive properties by modulating protein kinase C and tyrosine kinase activities ( 169 ). Among the various gangliosides, GD 3 is expressed on the cell surfaces of podocytes, metanephric mesenchyme, and interstitial cells alongside the stalk of the ureteric bud. The anti-GD 3 antibodies in vitro markedly inhibit tubulogenesis, suggesting that cell-cell contact in epithelial-mesenchymal interactions are crucial for metanephric development ( 151 ). The galectins are soluble -galactoside binding lectins. To date, 14 galectins have been isolated and characterized, and 2 galectins, galectin-3 and -9, are expressed in the kidney ( 25 ). Galectin-3 and -9 have opposing properties, i.e., apoptotic vs. antiapoptotic ( 20, 172, 177 ). Galectin-3, being antiapoptotic, is involved in cell growth, adhesion, and neoplastic transformation. Inclusion of anti-galectin-3 antibodies in the culture medium inhibits ureteric bud branching, suggesting a potential role in renal morphogenesis during embryonic development ( 20 ).( s. \7 v0 |7 m* v
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ECM-DEGRADING ENZYMES- k8 v: O: d* {1 i: A
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Besides ECM proteins, the biology of ECM-degrading enzymes is expectedly linked to metanephric development because they regulate expression of ECM protein by proteolytic processing and thus create an extracellular concentration in strategic locations with spatiotemporal distribution. As indicated above (see PGs ), PGs, having a concentration gradient, the highest being at the tips of the ureteric bud branches or epithelial-mesenchymal interface, maintain branching morphogenesis of the kidney ( 93, 96 ). With perturbation of this gradient at the tips, there is a failure in the dichotomization of ureteric bud branches. Such a concentration gradient of PGs in salivary glands, i.e., cleft vs. the advancing tips, is also believed to be responsible for their lobulogenesis ( 9 ).
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Other ECM glycoproteins that also exhibit such a concentration gradient include type III collagen, whose expression is highest in the cleft ( 119 ). These gradients may be due to their constitutive expression or to a relative local deficiency of degrading enzymes like collagenases or gelatinases. The gelatinases are collectively known as matrix metalloproteinases (MMPs) because their activity is dependent on the presence of metal ions, e.g., Zn 2  ( 95 ). To date, 23 MMPs have been identified, and among them 7 are of the membrane type (MT1-MT7-MMP) and the remaining are of the soluble type ( 118, 141 ). The latter are made up of a propeptide, a furin cleavage site, a catalytic domain containing Zn 2  and Ca 2  binding sites, and a hemopexin domain. The MT-MMPs have either a transmembrane domain (MT1-MT3, MT5) or they are glycosylphosphatidylinositol anchored (MT4, MT6) ( 64 ). At times, MT-MMPs activate soluble forms of MMPs; e.g., MT1-MMP activates pro-MMP2 to MMP2. In general, the MMPs can degrade a broad range of substrates, including collagens, proteoglycans, fibronectin, tenascin, entactin, elastin, fibrin, and fibrinogen ( 118, 141 ). Interestingly, their activity is inhibited by tissue inhibitors of metalloproteinases (TIMP-1-4), 2 -macroglobulin, and reversion-inducing cysteine-rich protein with Kazal motifs ( 7 ). Conceivably, these three groups of molecules, i.e., MMPs, MT-MMPs and TIMPs, as a trimolecular complex exert influence on a wide variety of biololgical processes, including branching morphogenesis of the kidney ( 77, 124 ) and possibly of the trachea, lung, and mammary gland ( 3 ). Their role in organotypical epithelial-mesenchymal interaction, as seen in nephrogenesis, was originally proposed more than three decades ago ( 58, 179 ), whereas the direct evidence implicating a differential gradient of collagen fragments initiating cleft formation and lobulogenesis was provided by Nakanishi and colleagues ( 47, 62 ). Their studies suggested that treatment with bacterial collagenase leads to branching dysmorphogenesis of the salivary glands ( 47, 62 ), whereas, on the other hand, collagenase inhibitors stimulated branching morphogenesis of the salivary glands ( 120 ). In lungs, enhanced gelatinase-A (MMP-2) activity in response to TGF- and EGF has been reported to inhibit arborization of the pulmonary alveoli ( 48 ). Conversely, increased expression of stromelysin-1 (MMP-3) in transgenic mice correlates with the accentuated lobulation of the mammary gland ( 162, 182 ). Along these lines, Ota and colleagues ( 124 ) noted increasing mRNA expression of MMP-2 in stromal cells and of MT-1-MMP in ureteric bud epithelia, respectively, during embryonic life. Such a distribution of MMP-2 and MT-1-MMP would be conducive to epithelial-mesenchymal interactions. Interestingly, their levels decreased during the postnatal period, suggesting that their potential role in organogenesis of the kidney in vitro is confined to the embryonic period ( 94 ). In subsequent studies using antisense techniques, Ota et al. ( 77 ) elucidated the roles of MMP-2 and MT-1-MMP in morphogenesis and suggested that MT-1-MMP, MMP-2, and TIMP-2, in a trimacromolecular complex, influence organogenesis of the embryonic kidney. However, it should be noted that anti-MMP-2 antibodies alone fail to inhibit organogenesis of the kidney ( 94 ). The failure to perturb renal morphogenesis by the latter may be due to the fact that anti-MMP-2 antibodies may not be of the blocking type. Nevertheless, MMP-9, expressed in the metanephros, has been shown to play a role in the organogenesis of the kidney in vitro ( 94 ). The role of MMP-2, MMP-9, and MT1-MMP has been suggested in tubular segmentation because they are expressed in specific segments of the nephron. The role of MMPs in organogenesis can be also extrapolated from studies of mouse inner medullary collecting duct cell (mIMCD3) culture systems. In these cell culture systems, Nigam and colleagues ( 146, 147 ) have been able to demonstrate a parallel rise or fall in the mRNA expression of MMP-2 with stimulation or inhibition of branching morphogenesis under the influence of TGF- or ligands of the EGF receptor, e.g., TGF-. Using a similar three-dimensional culture system, they also showed that metanephric mesenchyme cell-derived conditioned medium alters the transcription of MMP-2, -3, -9, MT1-MMP, and TIMP-2 along with the changes in ureteric bud branching morphogenesis ( 134 ). Despite the convincing data in in vitro studies, they had been difficult to reconcile with the results of in vivo studies. In this regard, MMP-9-deficient mice do not reveal any renal abnormalities ( 4 ). Moreover, intercrossing them with Col4a3 -deficient mice, a model of Alport syndrome, did not modify the progression of disease or integrity of the extracellular matrices. It is conceivable that the MMP-9 activity may be have been compensated for by other MMPs ( 92 ).
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Besides MMPs, there are certain other serine proteases that display ECM glycoprotein substrate specificities and are expressed in the fetal kidney and thus are believed to play a role in nephrogenesis, although the data are not so convincing. One of the important members of this family includes tissue-type plasminogen activator ( t-PA ), which has been localized to S-shaped bodies and glomeruli. Another one is urokinase type ( u-PA ), which is heavily expressed in renal tubular epithelia ( 150 ). Both t-PA and u-PA can induce proteolytic cleavage of glycoproteins either directly or indirectly by first activating latent MMPs. Using a three-dimensional collagen culture system, Orci and colleagues ( 128 ) showed that in vitro tubulogenesis of MDCK cells can be modulated by inhibitors of serine proteases, whose enzymatic activities and expression are regulated by hepatocyte growth factor ( 128 ). Hepatocyte growth factor is a morphogen, and its role in branching morphogenesis has been well documented in an in vitro metanephric organ culture system ( 183 ). Although these matrix-degrading serine proteases, i.e., t-PA or u-PA, are expressed in the embryonic metanephros as well as in renal tubules and modulate branching morphogenesis in vitro, both t-PA - and u-PA -deficient mice do not develop any aberrant renal phenotype ( 23 ).
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CONCLUSIONS" u& h+ Q  m& v

During renal organogenesis, there is remarkable cellular activity that is associated with inductive transformation of majority of the undifferentiated mesenchyme into an epithelial phenotype, followed by establishment of polarized epithelia with specialized junctions, and formation of a defined sculpted tissue mass in the form of tubules, which serve a number of absorptive and transport functions. At about the same time, a segment of the epithelial-mesenchymal mass undergoes vascularization, which then maturates into a capillarized structure known as the glomerulus, an organ with diverse biological functions, most importantly, the filtration of various macromolecules. To achieve such a high degree of complex organization of the functioning nephron, a diverse set of macromolecules exert a marked influence in a tightly regulated manner during the entire embryonic development of the metanephros. The role of these macromolecules has been heavily scrutinized over three last three decades, and a wealth of information has been generated, which has given deep insights into the cellular events that modulate renal organogenesis. The modulation seems to be an interplay among various ECM glycoproteins, ECM-degrading enzymes and their inhibitors, CAMs, integrins, growth factors and their receptors, and protooncogenes, all essential for the proper epithelial-mesenchymal interactions to take place so that nephrogenesis can proceed normally. Besides many of the known molecules that regulate branching morphogenesis/organogenesis, many new molecules have been added to the list during the last few years, and there are others that are expressed during embryogenesis whose functions are still to be clearly defined. They include crystallins (neuroectodermal lens proteins) ( 70 ), epimorphins (mesenchymal cell-surface proteins) ( 65 ), small PGs ( 15, 63 ), osteogenin ( 61 ), and matrillin ( 187 ). Also, there are other proteins, such as paxillin ( 166 ), an intracellular cytoskeletal protein, ADAMTS, and extracellular proteases ( 163 ), whose roles need to be delineated during epithelial-mesenchymal interactions and renal metanephrogenesis. The understudied area seems to be that of the oligosaccharides ( 45 ), which are involved in posttranslational modifications and thus conceivably would modulate morphogenesis by cell-cell or cell-matrix interactions. The galectins ( 25 ) are other hexose binding proteins that are not fully investigated as to their role in balancing growth vs. apoptotic potential, an essentiality in development. Finally, there are several other novel genes encoding mesenchymal or plasmalemmal proteins that are yet to be discovered in the fetal kidney, and they can be readily identified, first, by inducing dysmorphogenesis with various pathophysiological stimuli, such as glucose ( 75 ), followed by subjecting the embryonic metanephros to various subtraction hybridization analyses ( 87, 173, 175 ).
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GRANTS
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-28492 and DK-60635.

ACKNOWLEDGMENTS

The authors sincerely apologize if the work of any investigator has been left out by mistake and is not referred to in this manuscript.
      【参考文献】
Abrahamson DR, Prettyman AC, Robert B, and St. John PL. Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 63: 826-834, 2003.3 ]  Z4 j: ~0 u
1 I& e) ~0 C  |+ }' a- e
7 R. @/ l( u5 b4 \# t5 W+ A/ n
8 d' ^! w3 u7 t8 w' Q
Adamson ED. Growth factors and their receptors in development. Dev Genet 14: 159-164, 1993.

+ g( ?( u+ M% e" P1 g; z+ l
Affolter M, Bellusci S, Itoh N, Shilo B, Thiery JP, and Werb Z. Tube or not tube: remodelling epithelial tissues by branching morphogenesis. Dev Cell 4: 11-18, 2003.& e* [# a0 W; f+ y! z$ X8 q0 q
  f: x" t$ M2 [3 y; u
' ]# {3 ~6 ]% s, y% M2 q

Andrews KL, Betsuyaku T, Rogers S, Shipley JM, Senior RM, and Miner JH. Gelatinase B (MMP-9) is not essential in the normal kidney and does not influence progression of renal disease in mouse model of Alport syndrome. Am J Pathol 157: 303-311, 2000.

3 A, H2 V/ I7 W" D9 W# s
Aufderheide E, Chiquet-Ehrismann R, and Ekblom P. Epithelial-mesenchymal interactions in the developing kidney lead to expression of tenascin in the mesenchyme. J Cell Biol 105: 599-608, 1987.
, [, x/ N$ H9 X
" N4 {7 i* C7 R7 e1 ]
; {7 i- k9 o- t/ A" R
Avner ED, Ellis D, Temple T, and Jaffe R. Metanephric development in serum free organ culture. In Vitro 18: 675-682, 1982.

/ s" G+ O  y: u) G7 Q/ t; s

Baker AH, Edwards DR, and Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115: 3719-3727, 2002.
+ Y2 A% e, h( z7 V

7 O# B! |: d  [+ z. I$ ?
Balemans W and Van Hul W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol 250: 231-250, 2002.
1 T3 Q/ G; B; E) ]$ V5 i. R5 U
' c' J$ H$ x& Q8 E, ?
" H  u% Y. y8 M+ W
Banerjee SD, Cohn RH, and Bernfield MR. Basal lamina of embryonic salivary epithelia. Production by the epithelium and role in maintaining lobular morphology. J Cell Biol 73: 445-463, 1977.

* q, @( e; O' ]+ Y
7 U: p* _3 W5 w1 |, e
Bard JBL, Davies JA, Karavanova I, Lehtonen E, Sariola H, and Vainio S. Kidney development: the inductive interactions. Semin Cell Dev Biol 7: 195-202, 1996.
  S' }0 [2 h& |# X. D
1 m3 m9 O# `3 L  ^* s- N3 d
' N$ u* A0 L& X' i( N
Barondes SH, Cooper DNW, Gitt MA, and Leffler H. Galectins. Structure and function of a large family of animal lectins. J Biol Chem 269: 20807-20810, 1994.

Bernfield M, Banerjee S, Koda JE, and Rapraeger AC. Remodeling of the basement membrane: morphogenesis and maturation. Ciba Found Symp 108: 179-196, 1984.
1 Y: ~  [! e- w2 e4 `
/ F/ W. U* L8 ^9 D# d

Bernfield M, Hikes MT, and Gallo RL. Developmental expression of syndecans: possible function and regulation. Development Suppl : 205-212, 1993.0 M! W8 O: u  }- Z7 g0 `% N8 F

6 m/ P9 k5 c( ]

Bernstein J, Chen F, and Roszka J. Glomerular differentiation in metanephric culture. Lab Invest 45: 183-190, 1981.
  f3 C' s; X1 L$ ?. [
( W" C: b! Y3 Z( g% m& t3 }

Bianco P, Fisher LW, Young MF, Termine JD, and Robey PG. Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues. J Histochem Cytochem 38: 1549-1563, 1990.

Birchmeier C and Birchmeier W. Molecular aspects of mesenchymal-epithelial interactions. Annu Rev Cell Biol 9: 511-540, 1993.

7 F/ ~/ Q( U( ~9 q8 Z, a
: m8 ~5 E( \) L: \# v+ H# {& F
Bottinger EP and Bitzer M. TGF- signaling in renal disease. J Am Soc Nephrol 13: 2600-2610, 2002.& x* r5 m* E) u+ o; u1 J* a- t

4 u9 _1 t% A" w

Brandenberger R, Schmidt A, Linton J, Wang D, Backus C, Denda S, Muller U, and Reichardt LF. Identification and characterization of a novel extracellular matrix protein nephronectin that is associated with integrin 8 1 in the embryonic kidney. J Cell Biol 154: 447-458, 2001.# _3 ?2 S. ^. ]8 H
8 Q$ O/ \# h  i

Bullock SL, Fletcher JM, Beddington RSP, and Wilson VA. Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev 12: 1894-1906, 1998.

Bullock SL, Johnson TM, Bao Q, Hughes RC, Winyard PJD, and Woolf AS. Galectin-3 modulates ureteric bud branching in organ culture of the developing mouse kidney. J Am Soc Nephrol 12: 515-523, 2001.7 Q8 Q0 q- j$ ^$ _1 Y7 H
) j  _2 D' K; {+ p
; e8 Z1 X5 w( Y; ?
( F( v- D# v! v8 V- B# c
Burrow CR. Regulatory molecules in kidney development. Pediatr Nephrol 14: 240-253, 2000.

( G8 S, S( M/ l8 _' D* q9 E
. p% {8 H( J4 E' h
Campbell KP. Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage. Cell 80: 675-679, 1995.4 }$ d7 m5 Y! F! k5 }( ^
# A* r* u/ O; _+ o, W# _0 W* N

2 P( ^& k4 D" t5 d
Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, DeVos R, van den Oord JJ, Collen D, and Mulligan RC. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368: 419-424, 1994.

3 p8 Q0 k2 q( b
Cho EA, Patterson LT, Brookhiser WT, Mah S, Kintner C, and Dressler GR. Differential expression and function of cadherin-6 during renal epithelium development. Development 125: 803-812, 1998.

* o; o' Y9 a9 x$ ?# _
Cooper DNW. Galectinomics: finding themes in complexity. Biochim Biophys Acta 1572: 209-231, 2002.
- U7 N' e  N% O% [

! d& i0 C8 k; z9 o: [
Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, and Samuelson GC. Collagen COLL4A3 knockout: a mouse model for autosomal Alport syndrome. Gene Dev 10: 2981-2992, 1996.
3 Z' o, Y, M; V" D1 H# `
3 }( o4 U- j2 K, Y  G& Z

Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J, Brown R, Baldwin S, Kraemer P, Scheff S, Barthels D, Rajewsky K, and Wille W. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367: 455-459, 1994.

! A" ?1 _" a9 g9 P8 H9 v2 E' W
# z6 P; F; S3 N* P$ F9 G
Cunha GR. Role of mesenchymal-epithelial interactions in normal and abnormal development of mammary gland and prostate. Cancer Suppl 74: 1030-1044, 1994.
: j$ q) R; N5 h" w

9 w2 @; W! X' h% m( o* s  r
Dahl U, Sjodin A, Larue L, Radice GL, Cajander S, Takeichi M, Kemler R, and Semb H. Genetic dissection of cadherins function during nephrogenesis. Mol Cell Biol 22: 1474-1487, 2002.$ x  B! O- r6 e8 V4 |# ~
( X/ Z" j( {- V, }% r2 [

Damsky CH and Ilic D. Integrin signaling: it's where the action is. Curr Opin Cell Biol 14: 594-602, 2002.) Y# d: f& a* s' D' _

4 e$ O( n; K8 j! ]4 O
* t: \/ u  I7 K5 O8 ?* y3 Z# \' U
Debiec H, Christensen EI, and Ronco PM. The cell adhesion molecule L1 is developmentally regulated in the renal epithelium and is involved in kidney branching morphogenesis. J Cell Biol 143: 2067-2079, 1998.
" {' E) V: M/ i5 I7 f
) C" u2 t; K8 M9 u  I- N* e" H

Denda S, Reichardt LF, and Muller U. Identification of osteopontin as a novel ligand for the integrin 8 1 and potential roles for this integrinligand interaction in kidney morphogenesis. Mol Biol Cell 9: 1425-1435, 1998.( h/ i4 T4 X4 H- K% J

  g7 I4 m* e" s) }2 k
0 r! x0 J" v8 V6 t
Dudley AT, Lyons KM, and Robertson EJ. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Gene Dev 9: 2795-2807, 1995.
- k' d  A2 u0 O5 \* d" {* }" C

Durbeej M and Campbell KP. Biochemical characterization of the epithelial dystroglycan complex. J Biol Chem 274: 26609-26616, 1999.7 e1 ?! N  a# S5 B8 _, r; O

9 y# L/ q! l2 C& ]1 v

Durbeej M, Larsson E, Ibraghimov-Beskrovnaya O, Roberts SL, Campbell KP, and Ekblom P. Non-muscle -dystroglycan is involved in epithelial development. J Cell Biol 130: 79-91, 1995.
+ [: n, \# N8 ^, K6 u
  `: I- g3 J$ U" n
' I4 e+ ?8 f8 B  e
Ekblom P. Basement membranes in development. In: Molecular and Cellular Aspects of Basement Membranes, edited by Rohrbach DH and Timpl R. New York: Academic, 1993, p. 359-383.
+ r- `" o9 b: |7 r
9 M  p( S* ~0 ^

Ekblom P. Extracellular matrix and cell adhesion molecules in nephrogenesis. Exp Nephrol 4: 92-96, 1996.. R. [5 m. O: m  Q/ t. I( r  }) }

7 ]" R2 K. A9 J1 k4 U& E
! v6 _2 z! b9 N8 E, ~9 j. i
Ekblom P. Formation of basement membranes in embryonic kidney: an immuno-histochemical study. J Cell Biol 91: 1-10, 1981.
2 {3 |; T* E3 |* `* o! Z* n' ]

# d! R) T% Y. ?* @  ?
Ekblom P. Renal development. In: The Kidney, edited by Seldin DW and Giebisch G. New York: Raven, 1992, p. 475-501.! ~7 U, v- ~' \& L( t

! M, F% _0 N$ X/ r1 U' T" S$ {5 m( e
Ekblom P, Ekblom M, Fecker L, Klein G, Zhang H, Kadoya Y, Chu ML, Mayer U, and Timpl R. Role of mesenchymal nidogen for epithelial morphogenesis in vitro. Development 120: 2003-2014, 1994." ]! T) O. G' w# i6 z' [7 U8 n- p

: u9 ]6 W' {9 D( S
  w# G9 K% M4 g6 Y6 C! g6 i; m
Engel J. Structure and function of laminin. In: Molecular and Cellular Aspects of Basement Membranes, edited by Rohrbach DH and Timpl R. New York: Academic, 1993, p. 147-171.
- i) Y" x4 o- H  y/ a* u: \# `
8 U9 d  Q! O9 z/ T& G
* f: m4 p9 r9 ~* L5 g4 J2 u
Erickson AC and Couchman JR. Still more complexity in mammalian basement membranes. J Histochem Cytochem 48: 1291-1306, 2000.
9 C! I. I4 i- I; y! y
# [9 `* Y  B  h& w$ }2 f
1 w1 B9 U& O! ?( N8 E. A' _0 {# ^
Ervasti JM and Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 122: 809-823, 1993.* U2 P/ A: H, ~* Y! n1 u) V
6 h7 {# b9 \0 u: q1 H2 S2 R
6 ~& `! C% o# E4 ?+ t0 u" M
$ r1 ?; k7 X7 \  e& U' ~
Falk M, Salmivirta K, Durbeej M, Larsson E, Ekblom M, Vestweber D, and Ekblom P. Integrin 6 1 is involved in kidney tubulogenesis in vitro. J Cell Sci 109: 2801-2810, 1996.2 p9 n# F* z3 V8 x1 M) n
7 Q2 e9 f) O% Y4 }& V9 B

; O7 @1 r1 z# W3 _& {* E
Fleming S. N-linked oligosaccharides during human renal organogenesis. J Anat 170: 151-160, 1990.8 p1 [- Z" C' M
5 Q5 _/ d  ], J! H

- F/ Q9 a1 s( x3 P8 N
Fukai N, Eklund L, Marneros AG, Oh SP, Keene DR, Tamarkin L, Niemela M, Ilves M, Li E, Pihlajaniemi T, and Olsen BR. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 21: 1535-1544, 2002.

" M  U1 u# J% O9 R% u' w- q6 O' a1 P
% n3 ]( @+ n3 y& b1 V8 e* ^) v% J, E
Fukuda Y, Masuda Y, Kishi JI, Hashimoto Y, Hayakawa T, Nogawa H, and Nakanishi Y. The role of collagens in cleft formation of mouse embryonic submandibular gland during initial branching. Development 103: 259-267, 1988.+ ]% w6 c# U( k$ c7 V' |

Ganser GL, Stricklin GP, and Martisian LM. EGF and TGF- influence in vitro lung development by induction of matrix-degrading metalloproteinases. Int J Dev Biol 35: 453-461, 1991.

George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, and Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119: 1079-1091, 1993.
- x' H3 z! F4 `6 a

Gilbert T. Vitamin A and kidney development. Nephrol Dial Transplant 9: 78-80, 2002.

! a) Y% a& u: d( Y: M- K) m
Gladson CL and Cheresh DA. The v integrins. In: Integrins : The Biological Problems, edited by Takada Y. Boca Raton, FL: CRC, 1994, p. 83-89.# n* Q0 M. H/ n/ b5 S# k

" `5 q$ H" j# G) a8 u; o& l
Gomez AR, Norwood VF, and Tufro-McReddie A. Development of the kidney vasculature. Micro Res Tech 39: 254-260, 1997.8 Y/ F" h' y! `
2 K- \* o7 V  T1 m

Gossens CL and Unsworth BR. Evidence for a two-step mechanism operating during in vitro mouse kidney tubulogenesis. J Embryol Exp Morphol 28: 615-631, 1972.
+ D# X- ^  @2 `' p* m
4 x1 m8 q, p1 @, i. [

Grisaru S, Cano-Gauci D, Tee J, Filmus J, and Rosenblum ND. Glypican-3 modulates BMP- and FGF-mediated effects during renal branching morphogenesis. Dev Biol 231: 31-46, 2001.% T, `4 N6 |. `- f! q
  t1 Q+ q' j, i, w7 E9 z

) L6 z- m: a2 {/ K( Z( b
Grisaru S and Rosenblum ND. Glypicans and biology of renal malformations. Pediatr Nephrol 16: 302-306, 2001.4 A9 p0 X( g% E% u
" F4 V& r' h; f+ a- b# k
& w8 J1 ]3 a% \  S$ `
  S$ z* D  ?5 S% \
Grobstein C. Mechanism of organogenetic tissue interaction. Natl Cancer Inst Monogr 26: 279-299, 1967.5 l1 l& W! h9 k/ y; v' m" Z

. W. i6 d7 U* E5 p& Y
. w# Z1 k% `% u: V: Z
Grobstein C. Trans-filter induction of tubules in mouse metanephric mesenchyme. Exp Cell Res 10: 424-440, 1956., t. h" W' x( D0 L3 }" e( v1 d6 R; ?

0 I  X2 y/ g8 S

Grobstein C and Cohen J. Collagenase: effect on the morphogenesis of embryonic salivary epithelium in vitro. Science 150: 626-628, 1965.
/ x/ m: Z6 M5 `% |; v

Gumbiner B, Stevenson B, and Grimaldi A. The role of cell-adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex. J Cell Biol 107: 1575-1587, 1988.
6 M3 a. @7 u' ?$ x
* K* f3 a0 M. a# M+ `- u

Gumbiner BM. Regulation of cadherins adhesive activity. J Cell Biol 148: 399-403, 2000.- L/ a9 K6 m" z8 c% q# B5 R1 ~  n* ~  R
2 N) ]7 }) y8 F) H0 T& k

" ^% V7 F6 k. e! q* C- j0 s
Hardy G and Kramer B. Spatial and temporal localization of bone morphogenetic protein-3 (osteogenin) in the developing rat submandibular gland. SADJ 55: 136-141, 2000.. d" S3 E+ O& H8 \7 C2 [
4 l) e& A% E( ^1 N% G! G0 F
3 w+ e- ]' p2 ]/ f3 l; o# g4 b! J
1 ~& p: J; f1 W' W8 g% Q
Hayakawa T, Kishi JI, and Nakanishi Y. Salivary gland morphogenesis: possible involvement of collagenase. Matrix Suppl 1: 344-351, 1992.

- f7 ^0 \8 \3 e% \

Henry SP, Takanosu M, Boyd TC, Mayne PM, Eberspaecher H, Zhou W, de Crombrugghe B, Hook M, and Mayne R. Expression pattern and gene characterization of asporin. A newly discovered member of the leucine-rich repeat protein family. J Biol Chem 276: 12212-12221, 2001.
# n9 M* O: E' r0 U# \0 m; Z/ v6 f

Hernandez-Barrantes S, Bernardo M, Toth M, and Fridman R. Regulation of membrane type-matrix metalloproteinases. Semin Cancer Biol 12: 131-138, 2002.5 x# F. M0 [! F# ~* M" ?5 M% z+ Z( w8 D9 y
: _% q  a, Z- b3 H
, e- B6 I3 Z. o2 z
6 v$ _! Q; F/ z. V$ o
Hirai Y, Takebe K, Takashina M, Kobayashi S, and Takeichi M. Epimorphin: a mesenchymal protein essential for epithelial morphogenesis. Cell 49: 471-481, 1992.6 s' J; F8 U* `7 |3 x
: M0 ^4 m" X- c, Z6 Q6 B- E

Hogan BLM. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Gene Dev 10: 1580-1594, 1996.

Holthofer H, Henningar RA, and Schulte BA. Glomerular sialoconjugates of developing and mature rat kidneys. Cell Differ 24: 215-222, 1988.

; W- P9 ?$ C/ {) Z4 s

Howlett AR and Bissell MJ. The influence of tissue micro-environment (stroma and extracellular matrix) on the development and function of mammary epithelium. Epithelial Cell Biol 2: 79-89, 1993.5 z( e8 i' X+ w9 v

! A. H8 q7 t( h. |

Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 110: 673-687, 2002.

, r  z$ {/ [. @' Y% U) z
Iwaki T, Iwaki A, Liem RKH, and Goldman JE. Expression of B-crystallin in the developing rat kidney. Kidney Int 40: 52-56, 1991.1 H2 N' M/ Q* N0 d. S. d6 P
, D' P/ ]/ a, v; r! G8 r. }
/ R" Y: |& g3 D" ^* |) y6 \- |8 B

Kanwar YS, Carone FA, Kumar A, Wada J, Ota K, and Wallner EI. Role of extracellular matrix, growth factors and proto-oncogenes in metanephric development. Kidney Int 52: 589-606, 1997.
+ e/ q; C. d0 A" R% H
: e! v) z0 q5 ]& D
' z4 @8 }' t: V: ?) u8 K
Kanwar YS and Farquhar MG. Isolation of glycosaminoglycans from the glomerular basement membrane. Proc Natl Acad Sci USA 76: 4493-4497, 1979.' u# M- s0 I; S; D) O* b

2 I* e  q2 b& ?  z! P4 t3 s
; ?/ _. a  w8 k( |6 E
Kanwar YS and Farquhar MG. Presence of heparan sulfate in the glomerular basement membrane. Proc Natl Acad Sci USA 76: 1303-1307, 1979.
$ Q6 P) @8 L9 {3 f: b& n, Z
: k/ e5 U# |% D- f- w* M3 c
0 O7 a6 T6 q$ D
Kanwar YS, Kumar A, Yang Q, Tian Y, Wada J, Kashihara N, and Wallner EI. Tubulointerstitial nephritis antigen: an extracellular matrix protein that selectively regulates tubulogenesis vs. glomerulogenesis during mammalian renal development. Proc Natl Acad Sci USA 96: 11323-11328, 1999.

$ {& _( Z4 S5 x4 e) @

Kanwar YS, Liu ZZ, Kumar A, Usman MI, Wada J, and Wallner EI. Effect of high glucose on metanephric development. J Clin Invest 98: 2478-2488, 1996.

+ m' T/ V/ s, u4 R# r8 p- v7 _
( Q2 M! }7 C& q  g1 A  S$ X# q
Kanwar YS, Ota K, Yang Q, Kumar A, Wada J, Kashihara N, and Peterson DR. Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development. Am J Physiol Renal Physiol 275: F710-F723, 1998.
4 L5 M" X% E2 u% x% [
4 U# @# i& N+ |: v  v
6 H( N2 P6 M2 |, l6 q( C" t
Kanwar YS, Ota K, Yang Q, Wada J, Kashihara N, Tian Y, and Wallner EI. Role of membrane-type matrix 1 (MT-1-MMP), MMP-2, and its inhibitor in nephrogenesis. Am J Physiol Renal Physiol 277: F934-F947, 1999./ C3 ^$ g% v. n; p) ~! d7 A

6 ]0 @; a+ `/ [) j! ?! j2 x0 S
Karavanova ID, Dove LF, Resau JH, and Perantoni AO. Conditioned medium from a rat ureteric bud cell line in combination with bFGF induces complete differentiation of isolated metanephric mesenchyme. Development 122: 4159-4167, 1996.

9 O6 s5 i0 r# P3 ^7 _, r

Karihaloo A, Karumanchi SA, Barasch J, Jha V, Nickel CH, Yang J, Grisaru A, Bush KT, Nigam S, Rosenblum ND, Sukhatme VP, and Cantley LG. Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. Proc Natl Acad Sci USA 98: 12509-12514, 2001.
6 x7 @; ~7 u1 g  D3 ^, y- U8 e
% u) N, {9 k- a3 v
+ C2 g$ H0 ?/ h& \: q4 {
Klein G. Oncogenes. In: Cancer Medicine (3rd ed.), edited by Holland JF and Frei E. Philadelphia, PA: Lea & Febiger, 1993, p. 65-77.. y+ F3 |8 b  u+ U

; L* X& \, a! s1 o
/ r+ f- w. Q" P4 L
Klein G, Langegger M, Goridis C, and Ekblom P. Neural cell adhesion molecules during embryonic induction and development of the kidney. Development 102: 749-761, 1988.

3 C8 I0 F9 F  |2 n7 B% D+ v
; B/ g, I5 @3 V% o4 F% ^6 c
Kleiner DE and Stetler-Stevenson WG. Structural biochemistry and activation of matrix metalloproteinases. Curr Opin Cell Biol 5: 891-897, 1993.

1 J9 v/ R# D; _- V) d
' q6 _9 P$ i4 W5 i$ l: |2 m: V
Korhonen M, Ylänne J, Laitinen L, and Viratanen I. Distribution of 1 and 3 integrins in human fetal and adult kidney. Lab Invest 62: 616-625, 1990.5 t  H1 @+ a/ W4 `) E

# y" i1 Y7 H" P) H. Z8 }: j6 [& p

Korhonen M, Ylänne J, Laitinen L, and Viratanen I. The 1 - 6 subunits of integrins are characteristically expressed in distinct segments of developing and adult human nephron. J Cell Biol 111: 1245-1254, 1990.
$ a3 I  q3 S; ~

! q7 G! s% ]+ W1 h3 I" l
Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones R, and Jaenisch R. 3 1 Integrin has a crucial role in kidney and lung organogenesis. Development 122: 3537-3547, 1996.
- ?0 \  Z( `4 a+ B! {) Z* @' W

+ ?5 E) `4 G+ Q. E# m, e' k& x
Kreidberg JA and Symons JM. Integrins in kidney development, function and disease. Am J Physiol Renal Physiol 279: F233-F242, 2000.* s3 d, b5 R; m$ [$ H0 u2 _# r: @
3 ^+ b, c3 E, J; O; Z/ _8 f) c2 e
* H, E5 x: L3 t' ]: B! @' g

Kretzler M, Fan G, Rose D, Arend LJ, Briggs JP, and Holzman LB. Novel mouse embryonic renal marker gene products differentially expressed during kidney development. Am J Physiol Renal Fluid Electrolyte Physiol 271: F770-F777, 1996.

) k% A+ T  L3 X$ w% M- r8 ^
6 q! m: h/ b8 @, v- Y. z
Kries TE and Vale RD. Guidebook to Cytoskeletal and Motor Proteins. Oxford, UK: Oxford University Press, 1993.) s! d  [% g4 j- h
/ a5 s1 M  ]3 h. \" A5 h, N' h

Kumar A, Ota K, Wada J, Wallner EI, Charonis AS, Carone FA, and Kanwar YS. Developmental regulation and partial-length cloning of tubulointerstitial nephritis antigen of murine metanephros. Kidney Int 52: 620-627, 1997.& O4 M: S" |7 [, b. K; C+ f6 f
  A' X+ _9 L% e1 r' U$ _5 $ T" Q
  ^2 @, u; ]8 P+ w
' J8 v+ W/ i( N
Laitinen L, Viratanen I, and Saxen L. Changes in the glycosylation pattern during embryonic development of mouse kidney as revealed with lectin conjugates. J Histochem Cytochem 35: 55-65, 1987.& B3 {0 N5 ]& A1 K2 V
4 u; Y3 o* F5 A: M
* E% P, C, L0 d% O6 h, s% B- X( `
3 u4 v* ]) B9 C% B
Latchman DS. Transcription Factors. New York: IRL, 1993.

" v2 z0 U+ $ A8 \* r4 L+ D; q& l  y
Lelongt B, Legallicer B, Piedagnel R, and Ronco PM. Do matrix metalloproteinases MMP-2 and MMP-9 (gelatinases) play a role in renal development, physiology and glomerular disease? Curr Opin Nephrol Hypertens 10: 7-12, 2001.0 \* f+ O2 w+ F2 G) v
' }, W: d  f! B+ j! {) h9 \
% f) e5 _9 J7 C& A' j

Lelongt B, Makino H, Dalecki TM, and Kanwar YS. Role of proteoglycan in metanephric development. Dev Biol 128: 256-276, 1988.' E1 `- v; O% j% o% {
0 x% O" h/ ^; F6 c/ L

Lelongt B, Trugnan G, Murphy G, and Ronco PM. Matrix metalloproteinases MMP2 and MMP9 are produced in early stages of kidney morphogenesis but only MMP9 is required for renal organogenesis in vitro. J Cell Biol 136: 1363-1373, 1997./ N0 h* ]4 s  @) x" ?7 _
. k" p, Q# l+ ~8 s
5 w. u9 G5 [1 P) Y+ [
, U8 x3 h( D) K, s+ B
Lenz O, Elliot SJ, and Stetler-Stevenson WG. Matrix metalloproteinases in renal development and disease. J Am Soc Nephrol 11: 574-581, 2000.6 T$ t: {9 L* ~* D+ ]1 a! S- Q/ _2 A  b  p

+ V% ^& \  |. t0 q+ B" J+ t& ?, T
5 O: |: E5 D4 j1 v/ m* d
Liu ZZ, Dalecki TM, Kashihara N, Wallner EI, and Kanwar YS. Effect of puromycin on metanephric differentiation. Morphological, autoradiographic and biochemical studies. Kidney Int 39: 1140-1155, 1991.

Liu ZZ, Kumar A, Ota K, Wallner EI, and Kanwar YS. Developmental regulation and the role of insulin and insulin receptor in metanephrogenesis. Proc Natl Acad Sci USA 94: 6758-6763, 1997." m" |, V' f  n, ~
% \2 a: |* y. ]) x' }& ]5 S# Z$ T* M
( ^0 Y: S9 K6 @8 P, u. d3 _4 ^, @
" B; \7 T+ M5 O- _
Liu ZZ, Kumar A, Wallner EI, Wada J, Carone FA, and Kanwar YS. Trophic effect of insulin-like growth factor-I on metanephric development: relationship to proteoglycans. Eur J Cell Biol 65: 378-391, 1994.

0 |7 L' z+ }, I

Liu ZZ, Wada J, Alvares K, Kumar A, Wallner EI, and Kanwar YS. Distribution and relevance of insulin-like growth factor-I receptor in metanephric development. Kidney Int 44: 1242-1250, 1993.( Q9 Z1 X# e/ c* k; X. x; S7 g2 b

. ]. E; G' b9 n1 F# z
Liu ZZ, Wada J, Kumar A, Carone FA, Takahashi M, and Kanwar YS. Comparative role of phosphotyrosine kinase domains of c-ros and c-ret proto-oncogenes in metanephric development with respect to growth factors and matrix morphogens. Dev Biol 178: 133-148, 1996.

: m5 U1 ~- b! ~2 M# s4 C, d

Lo SH, Yu QC, Degenstein L, Chen LB, and Fuchs E, E. Progressive kidney degeneration in mice lacking tensin. J Cell Biol 136: 1349-1361, 1997.$ f3 u2 w' }" q  p; [
  N3 c. |3 I% W6 {+ n4 }" S: n0 }- x3 d

Lu W, Phillips CL, Killen PD, Hlaing T, Harrison WR, Elder FFB, Miner JH, Overbeek PA, and Meisler MH. Insertional mutation of the collagen types genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. Genomics 61: 113-124, 1999.

Luo G, Hofmann C, Bronckers ALJJ, Sohocki M, Bradley A, and Karsenty G. BMP-7 is an inducer of nephrogenesis and is also required for eye development and skeletal patterning. Genes Dev 9: 2808-2820, 1995.! C: f1 Q: x% F" U* s! ~

( `& Z* E2 N; q, U
$ `9 `5 E/ w; M& F
Mah SP, Saueressig H, Goulding M, Kintner C, and Dressler GR. Kidney development id cadherin-6 mutants: delayed mesenchyme-to-epithelial conversion and loss of nephrons. Dev Biol 223: 38-53, 2000.4 l& [; B. G! @+ u) z  F0 Z
5 b8 I9 w6 E: s$ W# Z
% F( w: d' z! X; Q* I% X+ t
$ I, u/ h- B  R/ b
Martinez G and Bertram JF. Organization of bone morphogenetic proteins in renal development. Exp Nephrol 93: e218-e222, 2002.

& F. O8 E% ]5 w8 l

Martinez G, Mishina Y, and Bertram JF. BMPs and BMP receptors in mouse metanephric development: in vivo and in vitro studies. Int J Dev Biol 46: 525-533, 2002.

Matrisian LM and Hogan BLM. Growth factor regulated proteases and extracellular matrix remodeling during mammalian development. Curr Top Dev Biol 24: 219-259, 1990.
8 p0 n& P( L* d0 g5 x4 {
5 Z" L& @7 [1 X6 |" t2 I" [

Miner JH. Developmental biology of glomerular basement membrane components. Curr Opin Nephrol Hypertens 7: 13-19, 1998.
! ]- G; F0 O5 z- ~% ?4 L

Miner JH. Renal basement membrane components. Kidney Int 56: 2016-2024, 1999.
; M" b& F2 q9 s& [, d# V( v/ J( D

) J6 p+ C: e( r+ Y5 n8 t
Miner JH and Li C. Defective glomerulogenesis in the absence of laminin 5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol 217: 278-289, 2000., W& ^1 Q: i1 C" X4 P" i

( m2 R. Q/ b+ u" U0 i; Y
' ?0 C) c; F% |
Miner JH and Sanes JR. Molecular and functional defects in kidneys of mice lacking collagen 3 (IV): implications for Alport syndrome. J Cell Biol 135: 1403-1413, 1996.

* q. Z2 _! ], B# b- g# D
Miosge N, Sasaki T, and Timpl R. Evidence of nidogen-2 compensation for nidogen-1 deficiency in transgenic mice. Matrix Biol 21: 611-621, 2002.5 h) p) e0 `/ X

Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, and Rosenthal A. Renal and neuronal mice lacking GDNF. Nature 382: 76-79, 1996.1 a& m- B6 K6 {0 ?" D4 P6 |, n

8 ^6 R8 l$ q- `1 J2 @5 R, H) P
3 K2 |7 j( g' [) l5 q
Morimura N, Tezuka Y, Watanabe N, Yasuda M, Miyatani S, Hozumi N, and Tezuka K. Molecular cloning of POEM: a novel adhesion molecule that interacts with 8 1 integrin. J Biol Chem 276: 42172-42181, 2001.6 Q+ B. P, U9 l+ X- d

Moulson CL, Li C, and Miner JH. Localization of lutheran, a novel laminin receptor, in normal, knockout, and transgenic mice suggests an interaction with laminin 5 in vivo. Dev Dyn 222: 101-114, 2001.8 ~! D* l  B- ]" ?9 y: b
2 f: B- W1 b+ n: h9 V- o. I/ N3 I5 M
, r9 ?; _4 o9 T* Y! ]3 X' E

Muller U, Wang D, Denda S, Meneses JJ, Pedersen RA, and Reichardt LF. Integrin 8 1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis. Cell 88: 603-613, 1997.

* h! ^5 h2 I4 z9 q  B
( q. {3 ~; H2 a: R  v1 \
Murshed M, Smyth N, Miosge N, Karolat J, Krieg T, Paulsson M, and Nischt R. The absence of nidogen-1 does not affect murine basement membrane formation. Mol Cell Biol 20: 7007-7012, 2000.
9 ~+ f: {+ m$ m, b

Nabeshima K, Inoue T, Shimao Y, and Sameshima T. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 52: 255-264, 2002., T$ ]7 a! P- b* S. ~3 D
+ a1 l8 W# q* j% \' e+ [# M9 ]3 u
* b% Q+ v) j3 P# j

Nakanishi Y, Nogawa H, Hashimoto Y, Kishi JI, and Hayakawa T. Accumulation of collagen III at cleft points of developing mouse submandibular epithelium. Development 104: 51-59, 1988.; v% H6 w  t& Y' E5 y; h6 o, _

9 m" T6 b: w) v0 Y
Nakanishi Y, Sugiura F, Kishi J, and Hayakawa T. Collagenase inhibitor stimulates cleft formation during early morphogenesis of mice salivary gland. Dev Biol 113: 201-206, 1986.
5 i6 |9 ?% L& K1 {( a' i0 T3 Z

Nathke IS, Hinck LE, and Nelson JW. Epithelial cell adhesion and development of cell surface polarity: possible mechanisms for modulation of cadherin function, organization and distribution. J Cell Sci Suppl 17: 139-145, 1993.
5 {( ]: v" R5 X9 v) ?* {) B: n
/ x$ l/ i( i2 h; a4 W% }$ e9 L% B
9 Q! ~5 H% G- w! }4 s4 u  }4 C6 b6 b
Noakes PG, Miner JH, Gautam M, Cunnigham JM, Sanes JR, and Merlie JP. The renal glomerulus of mice lacking s-laminin/laminin-2: nephrosis despite molecular compensation by laminin beta1. Nat Genet 10: 400-406, 1995.

: L' G6 X' M% g! Y" O& y1 a6 d" L
Olsen B. Life without perlecan has its problems. J Cell Biol 147: 909-911, 1999.* V' d4 g5 }2 ]6 |' v0 \7 t
- Y& e1 w3 Y4 d4 K0 }+ }- Y
! Q+ w/ V; Z* j( U

Ota K, Stetler-Stevenson WG, Yang Q, Kumar A, Wada J, Kashihara N, Wallner EI, and Kanwar YS. Cloning of murine membrane-type-1 matrix metallo-proteinase and its metanephric developmental regulation with respect to MMP-2 and its inhibitor. Kidney Int 54: 131-142, 1998.
. s  i, H5 {7 U& S! P3 @
3 Y' u9 S/ W7 }9 [7 ^
6 i5 k8 d, Q: H5 Y/ p
Ozawa M, Ringwald M, and Kemler R. Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci USA 87: 4246-4250, 1990.3 |' [& b, p. z  }/ i
3 _  Z9 G6 D  B. d2 N: }$ }
2 x1 A5 h2 a) T
/ i' D- p/ [) k  d" u
Pagani F, Zagato L, Vergani C, Casari G, Sidoli A, and Baralle E. Tissue-specific splicing pattern of fibronectin messenger RNA precursor during development and aging in rat. J Cell Biol 113: 1223-1229, 1991.

& V3 }" U( P- z  X/ g2 W+ O
Patarroyo M, Tryggvason K, and Viratanen I. Laminin isoforms in tumor invasion, angiogenesis and metastasis. Cancer Biol 12: 197-207, 2002.

Pepper MS, Matsumoto K, Nakamura T, Orci L, and Montesano R. Hepatocyte growth factor increases urokinase type plasminogen activator ( u-Pa ) and u-PA receptor expression in Madin-Darby canine kidney (MDCK) cells. J Biol Chem 267: 20493-20496, 1992.- Q# L! C% W9 o5 L0 j& B) ^6 T

5 A2 K6 `, V& d/ n# t" [. m5 |  X
Perantoni A, Dove LF, and Karavanova I. Basic fibroblast growth factor can mediate the early inductive events in renal development. Proc Natl Acad Sci USA 92: 4696-4700, 1995.: }1 b# A5 X  Y8 _
# S, o) O+ c( ^- x' }" V- V) i* _% U
( d3 Q5 c  a% G1 r7 r
/ F- @5 @) L+ A
Pfaff M, Gohring W, Brown J, and Timpl R. Binding of purified collagen receptors ( 2 1, 1 1 ) and RGD-dependent integrins to laminin and laminin fragments. Eur J Biochem 235: 975-984, 1994.
- t) v) r) I3 v/ ]) m
0 t. g, e! w& d" f
' z: W% i# p) |! a* a) b% y
Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, and Westphal H. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382: 73-76, 1996.+ H6 H! @1 W5 m9 g$ _

Pigot R and Power C. The Adhesion Molecule Facts Book. New York: Academic, 1993.
: W7 F2 D! G+ s3 H9 {

Platt JL, Trescony P, Lindman B, and Oegema TR. Heparin and heparan sulfate delimit nephron formation in fetal metanephric kidneys. Dev Biol 139: 338-348, 1990.
+ A9 O) t! T# k9 b  K0 E2 K; G1 x, L1 Z

Pohl M, Sakurai H, Bush KT, and Nigam S. Matrix metalloproteinases and their inhibitors regulate in vitro ureteric bud branching morphogenesis. Am J Physiol Renal Physiol 279: F891-F900, 2000.3 b9 q# l! N0 `! p& U9 z

: l' g5 V* v9 b8 u" e
: h' `9 |. F$ N$ `% l
Raats CJ, Van den Born J, Bakker MA, Oppers-Walgreen B, Pisa BJ, Dijkman HB, Assmann KJ, and Berden JH. Expression of agrin, dystroglycan and utrophin in normal renal tissue and in experimental glomerulonephritis. Am J Pathol 156: 1749-1765, 2000.! m9 ]. E8 s3 I& f
1 Q. f2 `2 B2 Y0 g
* {, k& k& Z& e) `. y8 ^; n8 ~

Robert B and Abrahamson DR. Control of glomerular capillary development by growth factor/receptor kinases. Pediatr Nephrol 16: 294-301, 2001.) }  n5 i  m; p1 E8 \
3 V* P3 z2 V) C
% s! Y$ [4 j& {! _" I

Rogers SA, Padanilam BJ, Hruska KA, Giachelli CM, and Hammerman MR. Metanephric osteopontin regulates nephrogenesis in vitro. Am J Physiol Renal Physiol 272: F469-F476, 1997., d& _; y3 E8 y8 N2 ^  K$ N; [

2 [# F; K% \) k' A+ ?, R9 ~% J' X9 s
; ~9 Q7 f2 g; `6 l, K" K8 Z
Rogers SA, Ryan G, and Hammerman MR. Insulin-like growth factors I and II are produced in the metanephros and are required for growth and development in vitro. J Cell Biol 113: 1447-1453, 1991.: y' Y' [% Z" h+ f- R; v. m6 ?" ?0 X

6 i) i/ c! d( J

Rogers SA, Ryan G, and Hammerman MR. Metanephric TGF- is required for renal organogenesis in vitro. Am J Physiol Renal Fluid Electrolyte Physiol 262: F533-F539, 1992.' r: I; m6 t* v# s4 L

  {  J  r% L2 a) c: I6 m0 l" [6 x

Rogers SA, Ryan G, Purchio AF, and Hammerman MR. Metanephric transforming growth factor- 1 regulates nephrogenesis in vitro. Am J Physiol Renal Fluid Electrolyte Physiol 264: F996-F1002, 1993.$ L/ f2 K$ x, B

6 g, T/ f4 |# G3 L

Rosenberg GA. Matrix metalloproteinases in neuro-inflammation. Glia 39: 279-291, 2002.
$ C" O% y8 a! w7 ?; B6 f! g

Ruoslahti E and Yamaguchi Y. Proteoglycans as modulators of growth factor activities. Cell 64: 867-869, 1991.! b* W2 @# p; r: d- m" E

6 S! w# G0 N0 j" e0 D$ ^3 k! Z& A% ]
Saelman EU, Keely PJ, and Santoro SA. Loss of MDCK cell 2 1 integrin expression results in reduced cyst formation, failure of hepatocyte growth factor/scatter factor-induced branching morphogenesis, and increased apoptosis. J Cell Sci 108: 3531-3540, 1995.

Saga Y, Yagi T, Ikawa Y, Sakakura T, and Aizawa S. Mice develop normally without tenascin. Genes Dev 6: 1821-1831, 1992.

9 B, n) P' D0 r  ~# H
Sakurai H, Barros EJ, Tsukamoto T, Barasch J, and Nigam SK. An in vitro tubulogenesis system using cell lines derived from the embryonic kidney shows dependence on multiple soluble growth factors. Proc Natl Acad Sci USA 94: 6279-6284, 1997.

/ H- w9 c" t* H$ H! f% V4 Q3 T, x
Sakurai H and Nigam SK. Transforming growth factor- selectively inhibits branching morphogenesis but not tubulogenesis. Am J Physiol Renal Physiol 272: F139-F146, 1997.

) [" T7 O" r+ R1 T; |/ M
Sakurai H, Tsukamoto T, Kjelsberg CA, Cantley LG, and Nigam SK. EGF receptor ligands are a large fraction of in vitro branching morphogens secreted by embryonic kidney. Am J Physiol Renal Physiol 273: F463-F472, 1997.9 h# ?. d- }( f8 i& D) D

7 z; ?. t2 a3 h
Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, and Barbacid M. Renal agenesis and absence of enteric neurons in mice lacking GDNF. Nature 382: 70-73, 1996.% l! s+ @8 B8 s- t- P3 M3 u

% u/ |# h! I( x* J7 O

Santos OFP and Nigam SK. HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-. Dev Biol 160: 293-302, 1993.

Sappino AP, Hurate J, Vassalli J, and Belin D. Sites of synthesis of urokinase and tissue-type plasminogen activators in murine kidney. J Clin Invest 87: 962-970, 1991.4 s2 d6 T! n0 [+ |

) k! l9 _4 O" V4 B* b. H

Sariola H, Aufderheide E, Bernhard H, Henke-Fahle S, Dippold W, and Ekblom P. Antibodies against cell surface ganglioside GD 3 perturb inductive epithelial-mesenchymal interactions. Cell 54: 235-245, 1988.' [7 u( |4 o% h$ |" n0 v) t. y
4 C! L2 M) L# v; T- Q
$ p+ a- f& w5 {# b; R, v/ o4 ~. a" q

Sariola H, Ekblom P, and Henke-Fahle S. Embryonic neurons as in vivo inducers of differentiation of nephrogenic mesenchyme. Dev Biol 132: 271-281, 1989.
4 e" w" d7 M: a# D
" X) m0 V. M$ j
% q8 ~4 D3 }* ]1 `3 H8 ^
Saxen L. Organogenesis of the Kidney. New York: Cambridge University Press, 1987.  u. F! p( `1 m( V; o; [( D, f
0 F, m& ^, r0 M( [

Schlessinger J and Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron 9: 383-391, 1992.

Schnabel E, Dekan G, Miettinen A, and Farquhar MG. Biogenesis of podocalyxin: the major glomerular sialoglycoprotein in the newborn rat kidney. Eur J Cell Biol 48: 313-326, 1989.1 Z1 m) c7 d- P- |! H

: g# e2 h6 h; |' W; O1 j* L
Schuchardt A, D'Agati V, Larsson-Blomberg L, Constantini F, and Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor ret. Nature 367: 380-383, 1994.

Sefton M, Johnson MH, and Clayton L. Synthesis and phosphorylation of uvomorulin during mouse early development. Development 115: 313-318, 1992.
# i+ r$ y7 e2 ]; s2 o* ^$ @
) \+ W" m. ]5 j& T2 P7 Q+ v
9 h, X+ @9 B$ {; R  |/ P; k! R
Shao X, Somlo S, and Igarashi P. Epithelial-specific Cre/lox recombination in the developing kidney and urinary tract. J Am Soc Nephrol 13: 1837-1840, 2002.

Sonnenberg A, Linders CJT, Modderman PW, Damsky CH, Aumailley M, and Timpl R. Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that 6 1 but not 6 4 functions as a major receptor for fragment E8. J Cell Biol 110: 2145-2155, 1990.4 W/ l0 z' E  @; n1 U* n

: g/ b6 Y/ v9 e+ Y
Sporn MB and Roberts AB. Peptide growth factors are multifunctional. Nature 332: 217-219, 1988.$ ?* s! Z, L1 G5 X" i

4 l7 }% @0 {, v* @0 J

Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA, and Damsky CH. Deletion of 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. GenesDev 9: 1883-1895, 1995.: u# i' @0 b$ o  p# A. s

Sympson CJ, Talhouk RS, Alexander CM, Chin JR, Clift SM, Bissell MJ, and Werb Z. Targeted expression of stromelysin-1 in mammary gland providesevidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol 125: 681-693, 1994.4 n* }' X* L; S8 s6 U7 V, D& S
( q0 B: E7 }8 f$ C  V1 C" @

Tang BL. ADAMTS: a novel family of extracellular matrix. Int J Biochem Cell Biol 33: 33-44, 2001.

6 W- K. A& {! f  V
! W6 O) f! r1 e/ p
Taub M, Wang Y, Szczesny TM, and Kleinman HK. Epidermal growth factor or transforming growth factor- is required for kidney tubulogenesis in matrigel cultures in serum-free medium. Proc Natl Acad Sci USA 87: 4002-4006, 1990.7 j0 N- W" d% h# B3 Y! t& U

Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M, Kilkenny C, Salazar-Grueso S, Pachnis V, Arumae U, Sariola H, Saarma M, and Inanez CF. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381: 785-789, 1996., e+ }  a4 o4 X7 o4 n: ]
! h& ?, s1 `: f( I5 q$ t7 w0 ?  ]* \4 N" a
7 `1 R' K2 P* ?2 A$ p( m

Turner CE. Paxillin interactions. J Cell Sci 113: 4139-4140, 2000.1 w  O1 ~) U/ Y7 j4 _% ^7 t
. [& G* c( I: Y; n  I

- z2 \& r& t, [! X' U7 d, V2 R; V
Ullrich A and Schlessinger J. Signal transduction by receptors with tyrosinase activity. Cell 61: 203-212, 1990.

2 Z# m0 N0 N/ l3 ?6 q
Vandenberg P, Kern A, Ries A, Luckenbill-Edd L, Mann K, and Kuhn K. Characterization of type-IV collagen major cell binding site with affinity for 1 1 and 2 1 integrins. J Cell Biol 113: 1475-1483, 1991.
/ J# n; \9 a# f5 j, W
& Q, e9 F2 a) ]

Van Echten G and Sandohoff K. Ganglioside metabolism. Enzymology, topology and regulation. J Biol Chem 268: 5341-5344, 1993.

Vestweber K, Kemler R, and Ekblom P. Cell-adhesion molecule uvomorulin during kidney development. Dev Biol 112: 213-221, 1985.. a* q  s8 ?1 C3 X4 S6 \& Q, b! R
+ \! U8 j& S% l* @) i" ^

Vukicevic S, Kopp JB, Luyten FP, and Sampath TK. Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci USA 93: 9021-9026, 1996.$ P) M1 U9 O( i* \- T

# H7 r9 d; P! P, a" `" u4 r

Wada J and Kanwar YS. Identification and characterization of galectin-9, a novel -galactoside-binding lectin. J Biol Chem 272: 6708-6086, 1997.

) Q+ y5 }! T5 L
Wada J and Kanwar YS. Characterization of mammalian translocase of inner mitochondrial membrane (Timm44) isolated from diabetic newborn kidney. Proc Natl Acad Sci USA 95: 144-149, 1998.
4 a# \# y3 S# H% \: F
9 {; o, I9 ^% U
% i" n# x, g6 q2 z+ n
Wada J, Kumar A, Liu Z, Ruoslahti E, Reichardt L, Marvaldi J, and Kanwar YS. Cloning of mouse integrin v cDNA and role of v -related matrix receptors in metanephric development. J Cell Biol 132: 1161-1176, 1996.

- i6 S+ h( j: ?' u/ E. N1 M+ e9 R  H, v
8 ]0 y  \8 e' s3 G. H
Wada J, Kumar A, Ota K, Wallner EI, Batlle DC, and Kanwar YS. Representational difference analysis of cDNA of genes expressed in embryonic kidney. Kidney Int 51: 1629-1638, 1997.& b" t$ V4 b4 t% j0 g

! l! D0 v/ |( e, z- S% f' h0 l
: ^& p% Q& V* Y5 `" y
Wada J, Liu ZZ, Alvares K, Kumar A, Wallner EI, Makino H, and Kanwar YS. Cloning of cDNA for the subunit of mouse insulin-like growth factor-I receptor and the role of the receptor in metanephric development. Proc Natl Acad Sci USA 90: 10360-10364, 1993.
. j4 J% I8 z: u# c
4 G0 Y' C7 s- b; m' Z5 L  f

Wada J, Ota K, Kumar A, Wallner EI, and Kanwar YS. Developmental regulation, expression and apoptotic potential of galectin-9, a -galactoside binding lectin. J Clin Invest 99: 2452-2461, 1997.

+ c, o- o2 I! d2 k% D" K

Warburton D, Lee M, Berberich MA, and Bernfield M. Molecular embryology and study of lung development. Am J Res Cell Mol Biol 9: 5-9, 1993.
3 w* L! F6 W' G/ m' L6 P
, E* v4 L' S4 t8 R* }0 f

Wessells NK and Cohen JH. Effect of collagenase on developing epithelia in vitro: lung, ureteric bud and pancreas. Dev Biol 18: 294-309, 1968.6 y& g& J: o5 `$ l1 X
% W: ]( h9 s# B# S
& s$ v& V- ~- J( M& ]5 h/ T& J
; ^' {' D& J/ O( _: g9 `
Wight TN, Heinegard DK, and Hascall VC. Proteoglycans: structure and function. In: Cell Biology of the Extracellular Matrix, edited by Hay ED. New York: Plenum, 1991, p. 45-71.
) s! E7 A, Y- Q9 E8 C! ^1 {
7 p! C% B) f: z1 a; t
2 q9 H: o* A+ H. `7 D# d7 `
Willem M, Miosge N, Halfter W, Smyth N, Janneti I, Burghart E, Timpl R, and Mayer U. Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development. Development 129: 2711-2722, 2002.

/ _* |5 o$ `# t& F. a- L
6 @+ E+ @% h$ }: D
Witty JP, Wright JH, and Martisian LM. Matrix metalloproteinases are expressed during ductal and alveolar mammary morphogenesis, and misregulation of stromelysin-1 in transgenic mice induces unscheduled alveolar development. Mol Biol Cell 6: 1287-1303, 1995.2 R7 Y' W- A0 i" ]" S* F; V& ~* t) u. |
7 A  K$ B. g- z
9 \" a# D; N' W0 `- ?
; Y2 c+ B7 i! D6 J
Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, Fine LG, Jat PS, Noble MD, and Gherardi E. Role of hepatocyte growth factor/scatter factor and met receptor in the early development of the metanephros. J Cell Biol 128: 171-184, 1995.
; M  T* |- L3 z8 `6 G4 |6 C

* f+ K. `+ X$ c( Z3 D/ |
Xiang YY, Tanaka M, Suzuki M, Igarashi H, Kiyokawa E, Naito Y, Ohtawara Y, Shen Q, Sugimura H, and Kino I. Isolation of complementary DNA encoding K-cadherin, a novel rat cadherin preferentially expressed in fetal kidney and kidney carcinoma. Cancer Res 54: 3034-3041, 1994.# [& ^/ k* ~- C- x0 L2 M

Yagi T and Takeichi M. Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev 14: 1169-1180, 2000.

' P- f0 Q- s* v2 }+ [! j
Zent R, Bush KT, Pohl ML, Quaranta V, Koshikawa N, Wang Z, Kreidberg JA, Sakurai H, Stuart RO, and Nigam SK. Involvement of laminin binding integrins and laminin-5 in branching morphogenesis of the ureteric bud during kidney development. Dev Biol 238: 289-302, 2001.( e0 K- @& ^7 |
0 Y4 [8 ^+ Y+ v& H! R; N
. K! y$ z# s; K$ d) J, ]+ P

Zhang Y and Chen Q. Changes of matrillin forms during endochondral ossification. Molecular basis of oligomeric assembly. J Biol Chem 275: 32628-32634, 2000.

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