Bernfield, M., S. Banerjee, J. E. Koda, and A. C. Raprae- ger. ..... 65: 378â391, 1994. 68. Liu, Z. Z., J. ... Pagani, F., L. Zagato, C. Vergani, G. Casari, A. Sidoli, and.
invited review Relevance of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis ELISABETH I. WALLNER,2 QIWEI YANG,1 DARRYL R. PETERSON,1 JUN WADA,1 AND YASHPAL S. KANWAR1 Departments of 1Pathology and 2Medicine, Northwestern University Medical School, Chicago, Illinois 60611 Wallner, Elisabeth I., Qiwei Yang, Darryl R. Peterson, Jun Wada, and Yashpal S. Kanwar. Relevance of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis. Am. J. Physiol. 275 (Renal Physiol. 44): F467–F477, 1998.—Mammalian nephrogenesis begins by the reciprocal interaction of the ureteric bud with the undifferentiated mesenchyme. The mesenchyme differentiates into an epithelial phenotype with the development of the glomerulus and proximal and distal tubules. At the same time, the mesenchyme stimulates the branching morphogenesis of the ureteric bud that differentiates into the collecting ducts. These inductive interactions and differentiation events are modulated by a number of macromolecules, including the extracellular matrix (ECM), integrin receptors, and cell adhesion molecules. Many of these macromolecules exhibit spatiotemporal developmental regulation in the metanephros. Some are expressed in the mesenchyme, whereas others appear in the ureteric bud epithelia. The molecules expressed in the mesenchyme or at the epithelial:mesenchymal interface may serve as ligands while those in the epithelia serve as the receptors. In such a scenario the ligand and the receptor would be ideally suited for epithelial:mesenchymal paracrine/juxtacrine interactions that are also influenced by RGD sequences and Ca21 binding domains of the ECM proteins and their receptors. This review addresses the role of such interactions in metanephric development. renal development; integrins
DURING EMBRYONIC LIFE, organogenesis proceeds by the differentiation and proliferation of multipotent cells leading to the formation of a defined sculpted tissue mass and is followed by a continuum of cell replication and terminal differentiation in most mammalian organs, with few exceptions, e.g., nervous system. These processes involve the participation of various extracellular matrix (ECM) glycoproteins (72), ECM receptors, i.e., integrins (84), cell adhesion molecules (CAMs) (12), intracellular cytoskeletal proteins (59), growth factors or hormones and their receptors (1), DNA-binding proteins (62), protooncogenes (52), and ECM-degrading enzymes and their inhibitors (53); as expected, the activities of this diverse group of macromolecules in fetal development are interlinked. 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 have been shown to be regulated by various growth factors or hormones and their receptors. Another set of macromolecules, i.e.,
CAMs, which influence intercellular adhesion and cell: cell (homotypic or heterotypic) interactions, are also the key participants in the morphogenesis of various organs during cell:matrix interactions (10). Finally, critical to cell behavior during differentiation, associated with organogenesis, is the fundamental process of phosphorylation of various integrins and hormone receptors or growth factor receptors that contain tyrosine or serine/threonine kinase intracellular catalytic domains (101, 113); the latter, as indicated above, are known to influence the expression of ECM proteins. The expression of various ECM proteins or their receptors varies considerably in different developing organ systems during embryonic life. This means that the macromolecules with restricted spatiotemporal genotypic or phenotypic expressions are relevant only to the morphogenesis of a particular organ system. Thus a morphogen is 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. Conceivably, differential concentration gradients of these macromolecules in various regions of the same develop-
0363-6127/98 $5.00 Copyright r 1998 the American Physiological Society
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ing tissue would induce different specific cellular events, thus adding complexity to the differentiation processes that ultimately lead to regional specialization within a given organ system. Finally, the magnitude of expression of various morphogenetic elements during fetal life would suggest that their function is specific for a given stage of a developing organ system. Although the expression of morphogens may be stage and tissue specific, a concerted coordination among the various macromolecules is critical for morphogenesis to proceed normally in the formation of a particular visceral organ. Information as to the role of various morphogenetic modulators has been derived from in vivo knockout experiments in mice as well as in vitro culture systems applicable to mammary (44), prostate (16), and salivary glands (6) and lung (123) and kidney (26, 100). In the morphogenesis of all these organ systems, the epithelial: mesenchymal or ligand:receptor interactions seem to be a common feature. Although the development of the mammalian metanephros represents a prototypic example of such interactions, there are certain distinct features that are unique to renal development and are discussed below. GENERAL FEATURES OF METANEPHRIC DEVELOPMENT
Renal development ensues following the sequential 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 (100). In mammals, the pronephros and mesonephros are rudiments of the nephrogenic cord, and it is the metanephros that matures to form a permanent kidney. In the mouse, metanephrogenesis commences at day 11 of gestation (100) by the interaction of the dorsally migrating ureteric bud, an epitheliallined tubular structure arising from the Wolffian duct, with the blastema, a loosely organized mesenchymal mass on the lateral aspect of the aorta in the most caudal segment of the nephrogenic cord. The migratory intercalation of the ureteric bud into the blastema is followed by differentiation of the mesenchyme into an epithelial phenotype and reciprocal inductive arborization of the ureteric bud and formation of the nascent nephrons. The nascent nephrons are formed by undergoing the following developmental stages: condensate/ vesicle, comma-shaped bodies, and S-shaped bodies (Fig. 1) (26, 100). The distal portion of the S-shaped body differentiates into various tubular segments, and it fuses with the ureteric bud branches, which form the collecting ducts of the kidney. The proximal portion of the S-shaped body develops into precapillary bodies, which upon vascularization by the processes of vasculogenesis (in situ blood vessel formation) and angiogenesis (sprouting of preexisting capillaries) form functioning mature glomeruli of the mammalian kidney. All these stages of renal glomerular and tubular development can be visualized in a histological section of the
Fig. 1. Schematic drawing depicting various stages of differentiation of the nephron. Formation of the nephron commences by interaction of the ureteric bud with loose metanephric mesenchyme. As a result, a condensate is formed, which goes through the comma-shape- and S-shape-body stages. This is followed by tubule elongation to form the precapillary stage nephric unit. The precapillary unit is vascularized by an ingrowth of extrarenal blood vessels leading to the formation of a mature glomerulus with an intricate capillary network (modified from Ref. 49).
newborn murine kidney, where the immature nephrons are situated underneath the renal capsule, whereas the most mature nephrons appear in the deeper cortex. Here, it needs to be mentioned that the processes of vasculogenesis and angiogenesis of the mammalian embryonic kidney are rather complex and are beyond the scope of this review, and the reader is referred to an excellent recent article by Hyink and Abrahamson (45). To gain insights into the developmental dynamics of the mammalian metanephros with respect to epithelial: mesenchymal or paracrine:juxtacrine interactions, investigators have resorted to in vitro techniques, including organ or cell culture systems. The cell culture system, e.g., MDCK cell lines, has been useful in studying the branching morphogenesis of tubules and the development of their epithelial junctions and polarity characteristics (76). Recently, a simple threedimensional cell culture system using a cell line derived from the embryonic mouse ureteric bud has been
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described to study the morphogenesis of kidney tubules (95). Utilizing this system, Sakurai et al. (95) successfully studied the influence of a large number of growth factors on the branching morphogenesis of the tubules. Similarly, the influence of various growth factors on tubulogenesis has been studied in another threedimensional Matrigel culture system in which baby mouse kidney cells were used (109). To study the morphogenesis of the whole kidney and of the glomerulus and tubules, Grobstein (37, 38) established an in vitro metanephric organ culture transfilter technique, which has been used widely with certain modifications (3, 8) for four decades by many investigators. In this culture system, various developmental stages, with the exception of vascularization of the metanephros, can be studied. The technique employs harvesting of either uninduced (day 10.5) or induced (day 11.5) metanephric mesenchyme, placing it on a microporous (,0.8 µm) filter, and maintaining it in culture for 7–10 days. In this system, the uninduced mesenchyme can be induced by placing ureteric bud or a heterologous inducer, e.g., embryonic neural tissue, on the bottom of the filter. The mesenchyme receives the inductive signals through the pores of the filter, perhaps by establishing pseudopodal cell-cell contacts (100). Once the mesenchyme is induced, morphogenesis of the nephrons proceeds normally even if the inducer is removed after only a brief exposure (100). The induced mesenchyme goes through a series of differentiation events leading to glomerulogenesis and tubulogenesis. Finally, fundamental to the inductive neotransformation of the mesenchyme are the macromolecules expressed at the epithelial:mesenchymal interface or ligands expressed in the mesenchyme and receptors in the ureteric bud epithelium that would be ideally suited for juxtacrine/ paracrine interactions (Fig. 2). The concept of such juxtracrine/paracrine interactions is discussed in this review with respect to cell:matrix interactions; also, an attempt is made to establish the relevance of other molecules that influence the expression of various ECM proteins and their receptors, i.e., growth factors, and consequently the development of the mammalian metanephros. ECM, ECM-DEGRADING ENZYMES, INTEGRINS, AND CAMS
Grobstein (37, 38) and Saxen (100) were the pioneers who laid down the foundation for the work to be pursued by numerous investigators on metanephric development. They postulated that the basement membrane (BM) of the ECM, sandwiched between the leading edge of the ureteric bud and the blastema, could exert a ‘‘paracrine’’ effect, which would facilitate the interactions between the two cell types and lead to an epithelial conversion of the mesenchyme and ultimately to the formation of the metanephros. Since the BM glycoproteins that induce branching morphogenesis are cytosecretory products of the native or neotransformed epithelium, the current belief is that the basal lamina also has a self-stimulatory or ‘‘autocrine’’ effect on the embryonic tissues during development. Al-
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Fig. 2. Schematic drawing depicting the reciprocal induction of mesenchymal cells and ureteric bud epithelia in embryonic kidney. The receptors of growth factors (GFs) and of extracellular matrix (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 (GDNF) and has been shown to be expressed in the metanephric mesenchyme (96, 111). Among the ECM proteins, some are expressed in the mesenchyme, while others are expressed at the epithelial: mesenchymal interface (modified from Ref. 69).
though the impetus for these studies evolved from the initial detection of constitutively expressed BM glycoproteins in the metanephric tissues, their simple presence and expression may not have a specific role at a given stage of embryonic development. Nevertheless, many functional studies, carried out by Ekblom (24, 26), Sariola et al. (99), Saxen (100), and others, have conclusively elucidated the morphogenetic role of certain ECM and ECM-related macromolecules in renal development. ECM PROTEINS
Various ECM molecules expressed during metanephric development are mesenchymal proteins, i.e., interstitial collagens, tenascin, nidogen (entactin), and fibronectin; and integral BM glycoproteins, i.e., type IV collagen, laminin, proteoglycans (PG), and tubulointerstitial antigen (TIN-Ag) (49). Some of the mesenchymal proteins, e.g., interstitial collagens, disappear at day 11 after induction, whereas the mRNA expression of others, e.g., the splice variants of fibronectin EIIIA, EIIIB, and V, decreases rapidly after day 15/16 of murine gestation (81). Although mesenchymal proteins are expressed in the metanephros, the role of the majority of them, with a few exceptions, remains elusive. For instance, anti-fibronectin antibodies are incapable of perturbing the conversion of mesenchyme to polarized epithelium. Although RGDS peptides that bind to the fibronectin receptor do reduce lobulations of embryonic lungs (24), they are ineffective in inhibiting metanephrogenesis (99). Also, no nephric defects in mice lacking
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fibronectin have been described (34). Tenascin is another mesenchymal protein that interacts with fibronectin and PGs, and it appears transiently around the condensates, S-shaped bodies, and tubules. Although its expression decreases if tubulogenesis is inhibited (2), no renal defects have been described in tenascindeficient knockout mice (92). Nidogen is a long-sought mesenchymal factor that seems to have a pivotal role in nephrogenesis. Nidogen is produced by mesenchymal cells, and it interacts with the g1-chain of laminin-1 (Fig. 3). This interaction, apparently, is crucial for the assemblage of the BM (27). Interestingly, disruption of the binding of the laminin-1 g1-chain to nidogen by a blocking antibody leads to inhibition of nephrogenesis in embryonic renal explants in culture (23). In contrast
Fig. 3. Schematic drawing of the model depicting interactions between the various chains of laminin-1, a6b1, a-dystroglycan, and mesenchymal cell-derived nidogen (entactin) during epithelial morphogenesis. Conceivably, integrin a6b1 and b-dystroglycan are involved in various transductional events, which 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 (modified from Ref. 22).
to the limited functional data on the mesenchymal proteins, the role of integral BM glycoproteins, e.g., laminin and PGs, and their receptors is more well defined in embryonic development. Type IV collagen and TIN-Ag exhibit a restricted spatiotemporal distribution in the developing metanephros; however, the functional data is not yet available (60). Last, although the integral BM proteins seem to appear simultaneously around the condensate, S-shaped bodies, glomerular capillaries, and tubules (25), the expression of their individual peptide chains is asynchronous. Laminin-1 is a high-molecular weight protein with a1-, b1-, and g1-chains organized into a cross-shaped structure. Its role in metanephric development has been well documented (11, 27). The expression of laminin chains during early development is asynchronous and is also species specific and stage specific (24). The mRNA expression of b1- and g1-laminin chains is detectable in vitro 24 h after the induction of nephrogenesis in mice. In contrast, the expression of the a1-chain appears only after 2 days, coinciding with the appearance of polarized epithelia in the comma- and S-shaped bodies, and is gradually lost from the ureter, distal tubules, and glomerular BM (GBM). Evidence for a direct role of laminin in in vitro nephrogenesis was elucidated by using elastase-generated peptides and chain-specific antibodies, i.e., against the carboxy ends of a1-chains (E3) and a1-b1-g1-chains (E8), the amino terminus of b1-chains (E4), and the central region of the whole laminin molecule containing the YIGSR-dependent laminin receptor binding sites (Fig. 3) (24). The antibodies against E3, the heparin binding domain more recently found to bind to the dystroglycan complex (see INTEGRINS AND OTHER ECM RECEPTORS), and E8, the a6b1-integrin receptor binding site (105), inhibited the morphogenesis and formation of polarized epithelium, whereas antibodies against the central region of the laminin molecule did not perturb renal development (24). Interestingly, antibodies directed against the central regions of laminin do perturb morphogenesis of the lungs (24). During development, other roles of laminin include angiogenesis and integrin-receptormediated attachment, with the activities confined to YIGSR sequences of laminin b1-chain and RGD sequences of the a1-chain, respectively (27). The expression of a1-chain is confined to larger blood vessels (24), whereas that of the b2-chain is confined to capillaries of the mature renal glomeruli. Such stage-specific isoforms or switches in their expressions are also seen in other proteins that regulate development, e.g., PGs. PGs play a significant role in the morphogenesis of several tissues (126). The PGs are made up of glycosaminoglycan (GAGs) chains that are bound by Oglycosidic linkage to the core peptide. A number of different types of PGs are expressed in the kidney, including heparan sulfate-proteoglycan (HSPG) (63), chondroitin sulfate-proteoglycan (CSPG) (50), and decorin and biglycan (9). The basal lamina-specific HSPG is known as perlecan (78), whereas those that are cell membrane bound belong to the family of syndecans (7). The latter are present in the mesen-
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chyme and early differentiating epithelium, and they gradually disappear with the maturation of the nephron (7). Initially, at the time of induction, the sulfated PGs are highly concentrated at the ‘‘tips’’ of the ureteric bud branches, i.e., the epithelial:mesenchymal interface and the site where nascent nephrons are formed. Later on, they are seen around the condensate and persist in the BMs throughout the fetal and neonatal periods (63). Inhibition of synthesis of sulfated PGs by puromycin or addition of GAG chains onto the core peptide is associated with blunting of the tips of ureteric bud branches and dysmorphogenesis of the kidney (63, 65). Incidentally, addition of heparin sulfate, and not heparan sulfate, to culture medium also inhibits nephrogenesis (85). Thus it appears that the biological actions of PGs are mediated via their GAG chains. This notion has been supported by the experiments with salivary glands, where enzymatic deletion of GAGs was shown to inhibit lobulogenesis (4). The GAG chains can interact with other matrix molecules, such as the E8 fragment of laminin (105), and they also act as reservoirs for various growth factors, e.g., basic fibroblast growth factor (90), and thus can influence morphogenesis by more than one mechanism. Some of the growth factors or their receptors which have been shown to modulate the expression of PGs and are linked to the morphogensis of the kidney include insulin, insulin-like growth factor-I (IGF-I), and transforming growth factor-a (TGF-a) and -b (TGF-b) (56, 66–68, 87–89, 121). Conceivably, the epithelial:mesenchymal interactions also take place among these molecules, since the ligands, like insulin or IGF-I, are expressed in the mesenchyme while their receptors are in the ureteric bud epithelia, and both of these display a restricted spatiotemporal distribution during metanephric development (66, 68, 121). The addition of IGF-I or insulin into the organ culture medium leads to hypertrophy/hyperplasia of the metanephric explants, concomitant with an increase in mRNA and protein expression of the PGs (66, 67). On the other hand, gene disruption of the IGF-I or insulin receptors by addition of antisense oligonucleotides in organ culture leads to atrophy of the explants with markedly decreased expression of the PGs, especially at the tips of the ureteric bud branches, the site where epithelial:mesenchymal interactions take place (66, 121). Similarly, gene disruption of the glial cell linederived neurotrophic factor (GDNF) receptor, i.e., c-ret protooncogene with a phosphotyrosine kinase catalytic domain (111), leads to a remarkable dysmorphogenesis of the kidney concomitant with a dramatic decrease in the expression of ECM proteins, in particular, that of the PGs (69). Conceivably, GDNF, a molecule related to the TGF-b superfamily, is expressed in the mesenchyme, whereas c-ret is in the ureteric bud epithelia, and in vivo gene disruption of either of these also leads to the agenesis or hypogenesis of the kidney (96, 103). This scenario again reemphasizes the importance of epithelial:mesenchymal interactions in renal development. Here it is relevant to mention the role of another matrix protein, i.e., bone morphogenetic protein-7
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(BMP-7), in renal development. BMP-7 belongs to the TGF-b superfamily and is involved in the mineralization of cartilage (42). Its spatiotemporal mRNA expression in the metanephros is somewhat controversial. Dudley et al. (19) reported that at day 14.5 of gestation, BMP-7 mRNA transcripts are expressed in the mesenchyme of the nephrogenic zone, the condensing aggregates, and the epithelia of comma- and S-shaped bodies, with a weaker expression in the ureteric buds. However, Luo et al. (71) and Vukicevic et al. (117) reported that at day 12.5, BMP-7 mRNA is expressed in both the ureteric bud and condensed mesenchymal cells around these and at day 14.5 in the condensing aggregate, comma- and S-shaped bodies, and vascularized glomeruli. These differences appear to be related to the time of gestation at which the tissues were examined and how rigorously the tissues were processed for in situ hybridization. Nevertheless, these studies do not in any way undermine the role of BMP-7 in metanephric development, since two independent studies indicate that BMP-7-deficient mice exhibit hypogenesis/agenesis of the kidney, in addition to anomalies of the eye and skeletal systems (19, 71). Here, it is worth mentioning that since BMP-7, a member of TGF-b superfamily, modulates the synthesis of PGs (31), it is conceivable that the effects of BMP-7 on the metanephric development are mediated via the PGs. Further evidence that TGF-b, a modulator of the expression of PGs, plays a role in nephrogenesis is derived from cell culture studies, where TGF-b was found to perturb tubulogenesis of MDCK cells grown in collagen gels (97). The mechanism by which TGF-b modulates the expression of PGs is rather complex. TGF-b seems to exert its influence via about nine binding proteins or receptors, and among them the first three are well characterized. Type I and II receptors contain serine/ threonine kinase domains. Upon their heterodimerization, there is an activation of the Mad (‘‘mothers against dpp’’) signaling pathway leading to target gene expression. The type III receptors are made up of endoglin and betaglycan, and both are transmembrane PGs with serine and threonine residues, which are likely to be phosphorylated by protein kinase C and would be expected to influence the expression of the target genes. For a detailed discussion of TGF-b signaling pathways, there is a recent excellent review by Derynack and Feng (18). ECM-DEGRADING ENZYMES
From the above discussion, it seems that a concentration gradient of PGs, with the highest content being at the tips of the ureteric bud branches or epithelial: mesenchymal interface, is necessary to maintain nephrogenesis. A similar concentration gradient of PGs in salivary glands, i.e., cleft vs. the advancing tips, is thought to be responsible for their lobulogenesis (4). Such concentration gradients also are observed for other ECM glycoproteins, e.g., type III collagen, whose expression is highest in the cleft (75). These gradients may be due to their constitutive expression or to a relative local deficiency of degrading enzymes like
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collagenases or gelatinases. The latter are collectively known as matrix metalloproteinases, and they are zinc metal-dependent proteolytic enzymes (107, 124). Their role in organotypic epithelial:mesenchymal interaction was originally proposed three decades ago by Grobstein and Cohen (36) and Wessells and Cohen (125). Direct evidence implicating a differential gradient of collagen fragments initiating cleft formation and lobulogenesis was provided by studies in which treatment with bacterial collagenase perturbed the branching morphogenesis of salivary glands (32, 40). In contrast, collagenase inhibitors stimulated branching morphogenesis of the salivary glands (74). In lungs, an enhanced gelatinase-A (matrix metalloproteinase-2, MMP-2) activity, in response to TGF-a and epidermal growth factor (EGF), has been reported to inhibit arborization of the pulmonary alveoli (33). Conversely, increased expression of stromelysin-1 (MMP-3) in transgenic mice correlates with the accentuated lobulation of the mammary gland (108, 127). Along these lines, the increasing mRNA expression of MMP-2 in stromal cells and of membrane type-1 MMP (MT-1-MMP) in ureteric bud epithelia during embryonic life, and decreasing levels during the postnatal period may suggest their role in the organogenesis of the kidney (79). Such a distribution of MMP-2 and MT-1-MMP would be conducive for the epithelial:mesenchymal interactions to take place. Moreover, it is conceivable that it is the trimacromolecular complex of MT-1-MMP:MMP-2:TIMP-2 (TIMP-2 is the tissue inhibitor of MMPs) that may influence the morphogenesis of the embryonic kidney (79). However, it should be noted that the anti-MMP-2 antibodies fail to inhibit the organogenesis of the kidney (64). 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 (64). The role of MMPs in organogenesis can be also extrapolated from studies on MDCK cell culture systems. In these cell culture systems, Nigam and colleagues (93, 94) have been able to demonstrate a parallel rise or fall in the mRNA expression of MMP-1 with stimulation or inhibition of branching morphogenesis under the influence of TGF-b or ligands of the EGF receptor, e.g., TGF-a. Other matrix-degrading enzymes, which conceivably may play a role in nephrogenesis, include various serine proteases. Among these, tissue-type plasminogen activator (tPA) has been localized to Sshaped bodies and glomeruli, whereas the urokinasetype (uPA) has maximal gene expression in renal tubular epithelia (98). Both tPA and uPA can degrade ECM either on their own or by activating latent MMPs. Although these matrix-degrading proteases are expressed in the embryonic kidneys, mice lacking tPA and uPA do not reveal any embryological abnormalities (14). However, in vitro, the tubulogenesis of MDCK cells is inhibited by inhibitors of serine proteases, whose enzymatic activities and expression are modulated by a known morphogen, i.e., hepatocyte growth factor (82).
INTEGRINS AND OTHER ECM RECEPTORS
Integrins are transmembrane, heterodimeric, noncovalently bound glycoprotein complexes consisting of aand b-chains, are widely distributed in various tissues, and mediate diverse biological functions including cellcell and cell-matrix interactions, cell polarity, cell migration, and angiogenesis (84). More than 20 integrins have been discovered in various tissues, and these serve as receptors for various morphogenetic ECM proteins, e.g., laminin-1. Although both chains participate in divalent cation-dependent and peptide-sequencespecific ligand binding, the a-subunit largely determines the substrate specificity with ECM proteins. The intracytoplasmic tail of the b-chain is responsible for its interactions with the cell cytoskeleton via binding to talin, vinculin, and a-actinin and may be also involved in transductional events, since certain b-subunits contain tyrosine phosphorylation sites (84). In the metanephros, integrin exhibits spatiotemporal expression. Among the b1-integrins, a1b1 and a4b1 are expressed in the uninduced mesenchyme, whereas a3b1, a2b1, and a6b1 are distributed at the interface between the basal lamina and the plasmalemma of the foot processes of developing podocytes, endothelia, and tubular epithelium, respectively (54, 55). The a6-subunit, expressed in the cells of the condensing mesenchyme and polarized tubular epithelium, codistributes with the laminin a1-chain. The a6b1-integrin serves as a receptor for the E8 fragment of a1-b1-g1-chains of laminin (Fig. 3), and, like the E8 laminin-1 fragment, anti-a6 antibodies also perturb the formation of polarized nephric epithelium and branching morphogenesis of salivary glands and tubulogenesis of the metanephros in vitro (24, 29). In addition to a6b1, a2b1 and a3b1 also bind to laminins, and a2-integrin is expressed in the distal tubules, with a3 in the maturing glomerular podocytes (22). Although a2b1 binds to laminin, its binding affinity to type IV collagen is much higher (83, 114). Since type IV collagen is present during early stages of tubule formation and maturation of nephrons, it is likely that its interaction with a2b1 is physiologically relevant in renal tubulogenesis. The notion that integrins play a role in metanephric development is also supported by in vivo knockout experiments. The most interesting results have been obtained with the gene disruption of the a8-subunit of a8b1-integrin, as a consequence of which an almost complete arrest of nephrogenesis was observed (73). Although a target mutation in the integrin a3 gene does not lead to agenesis/hypogenesis of the embryonic kidney, some degree of growth retardation of the metanephros is observed (57). Along these lines, in vitro gene disruption of a2b1-integrin leads to a failure in the branching morphogenesis of tubules in the MDCK cell collagen gel culture system (91). Since the E8 fragment of laminin-1 also interacts with a3b1- and a7b1integrins, it would suggest that their common b-subunit may also have a functional role in morphogenesis (55). In this regard, anti-b1 antibodies have been shown to cause functional impairment in mammary epithelia
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and block the differentiation of colon carcinoma cells and the formation of glandular structures in threedimensional collagen gels (24). The role of b1 in nephrogenesis has received limited attention (29), but its in vivo gene disruption is associated with peri-implantation lethality (106). Among the av-related integrins, avb3 has been reported to be present on the endothelial cells of glomerular and extraglomerular capillaries (55). The avb3 binds to a number of ligands including vitronectin, fibrinogen, von Willebrand factor, thrombospondin, fibronectin, osteopontin, bone sialoprotein, thrombin, laminin, and collagens type I and IV (35). With such a broad range of interactions, one would expect avb3 to participate in diverse biological functions, particularly in angiogenesis. Its relevance to renal angiogenesis, however, remains to be investigated. Certainly, av-related integrins do play a role in metanephric development, as assessed by gene disruption with the inclusion of av-specific antisense deoxyoligonucleotides in the metanephric culture system (119). Dystroglycan complex is another recently discovered ECM receptor molecule that seems to be relevant to the morphogenesis of the mammalian kidney (Fig. 3). The dystroglycan complex is made up of several proteins forming a transmembrane linkage between muscle laminin and the cytoskeleton (13, 28). The complex includes six proteins, i.e., a- and b-dystroglycans, a-, b-, and g-sarcoglycans, and a 25-kDa protein. The a-dystroglycan is extracellular, and it binds to E3-like G domains of laminin-2 in muscle and possibly interacts with laminin-1 as well. The b-dystroglycan, which is transmembrane, binds to the COOH terminus of intracellular dystrophin, and the NH2 terminus of the latter has binding affinities with F-actin. By in situ hybridization, it has been shown that dystroglycan and laminin a1-chains are coexpressed in epithelial components of the developing metanephros, and both exhibit a restricted spatiotemporal distribution (21). Since extracellular a-dystroglycan interacts with the E3 domain of laminin a1-chain that regulates morphogenesis of the kidney, it is conceivable that the dystroglycan complex plays some role in renal development. Indeed, inclusion of monoclonal antibodies, which are known to block the binding of a-dystroglycan to laminin-1, in culture perturb the morphogenesis of the developing metanephros, in particular, that of the differentiating epithelium (21). The relevance of this newly discovered ligand: receptor interaction reinforces the original contention of Grobstein (37) as to the significance of epithelial: mesenchymal interactions in metanephrogenesis.
chyme. L-CAM (E-cadherin 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 laminin a1-chain, thus suggesting its potential role in tubulogenesis. However, antibodies to both L-CAM and N-CAM do not inhibit the conversion of mesenchyme to an epithelial phenotype of the metanephros (51, 116) or affect the morphogenesis of MDCK cells (39). Also, N-CAM-deficient mice do not exhibit any renal abnormalities (15). Incidentally, anti-uvomorulin antibodies perturb compaction at the 8- to 16-cell stage of the primitive embryonic tissues, which may be due to interference with protein kinase C-dependent phosphorylation (104) and disruption of uvomorulin:actin interactions mediated via a- and b-catenins, which associate with the intracytoplasmic domain of uvomorulin (80). Another CAM, a prototype of class II cadherin is K-cadherin. K-cadherin is specifically expressed in the kidney, and it mediates Ca21-dependent homophilic cell aggregation (128); its role in nephrogenesis remains to be investigated. Tensin is another newly discovered F-actin binding protein and is expressed in the kidney; however, it regulates postnatal renal development only (70). Thus it is not clear whether the actin binding proteins are essential to the organogenesis of the embryonic kidney. It would be interesting to investigate whether the proteins that do not bind to actin, e.g., Dp140 (a product of Duchenne muscular dystrophy locus), and are expressed in the embryonic metanephros (20) have any role in renal organogenesis. Sialoconjugates (43, 61), including podocalyxin (102), and sialylated glycosphingolipids (gangliosides) (99), as well as many other N-linked oligosaccharides (30) are expressed in the kidney. Podocalyxin may be the major sialoglycoprotein in the developing glomerular epithelium involved in podocyte-GBM interactions (102). The gangliosides are ubiquitously distributed in various tissues and display cell-cell and cell-substratum adhesive properties by modulating protein kinase C and tyrosine kinase activities (115). Two gangliosides of interest are GD2 and GD3. GD3 is expressed on welldifferentiated podocytes, metanephric mesenchyme, and interstitial cells near the stalk of the ureter. Since GD3 is expressed at the cell surfaces and its antibodies markedly inhibit tubulogenesis, this suggests that cell: cell contact in epithelial:mesenchymal interactions is crucial for metanephric development (99).
CAMs AND SIALOGLYCOCONJUGATES
CONCLUDING REMARKS
CAMs are integral plasma membrane glycoproteins like integrin receptors or the dystroglycan complex and may play a role in metanephric development. They may be involved in the increased adhesiveness of cells to form condensates around the ureteric bud branches during development. Two types of CAMs, i.e., neural (N-CAM) and liver (L-CAM), are expressed in the kidney (51, 116). The N-CAM, a heavily sialyated glycoprotein, is distributed in the uninduced mesen-
Renal morphogenesis constitutes a defined period of intense cellular activity, inductive transformation of undifferentiated cells to polarized epithelia, ingrowth of capillaries into an intricate parenchymal epithelialmesenchymal mass, and finally the maturation into an organ with diverse structural and biological functions. A large number of factors are operative, in a defined sequence during nephrogenesis, which are tightly regulated to attain a successful outcome, that is, the genesis
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of functioning nephrons. During the last 2-3 decades, a wealth of information has been generated that allows us to have a greatly expanded insight into the overall cellular events relevant to renal organogenesis. It should be emphasized that modulation of the interactions between various ECM glycoproteins, ECMdegrading enzymes and their inhibitors, CAMs, integrins, and growth factors and their receptors are required for proper epithelial:mesenchymal interactions essential to the normal processes of nephrogenesis. Considerable progress has been made, and the roles of such macromolecules have been elucidated in renal development over the last few years. The list is rapidly growing, and the roles of other matrix or plasmalemmal proteins, which are expressed in the kidney, require delineation, e.g., crystallins (neuroectodermal lens proteins) (48), osteopontin (2ar) (77), SPARC (secreted protein, acidic and rich in cysteine), also known as osteonectin and BMP-40 (47), epimorphins (mesenchymal cell-surface proteins) (41), polycystin (46a), the hedgehog family of proteins (46), and yet-to-be-described other mesenchymal or epithelialderived molecules. Similarly understudied and requiring attention, the molecules that may regulate matrix protein expression and consequently the renal vasculogenesis/angiogenesis include tyrosine kinase receptors, flk-1 and ELK, and their putative ligands, VEGF and LERK-2 (17, 86, 112). Also, there are several other novel genes encoding mesenchymal or plasmalemmal proteins that have been discovered in the embryonic kidney by differential-display and -representation techniques (58, 120), and their role in metanephric development remains to be investigated. Finally, another area of considerable interest is that which includes the molecules that are developmentally regulated in several organ systems and interact with matrix proteins, e.g., galectins (5, 118, 122). This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-28492. Address for reprint requests: Y. S. Kanwar, Dept. of Pathology, Northwestern Univ. Medical School, 303 E. Chicago Ave., Chicago, IL 60611. REFERENCES 1. Adamson, E. D. Growth factors and their receptors in development. Dev. Genet. 14: 159–164, 1993. 2. Aufderheide, E., R. Chiquet-Ehrismann, and P. Ekblom. Epithelial-mesenchymal interactions in the developing kidney lead to expression of tenascin in the mesenchyme. J. Cell Biol. 105: 599–608, 1987. 3. Avner, E. D., D. Ellis, T. Temple, and R. Jaffe. Metanephric development in serum-free organ culture. In Vitro (Rockville) 18: 675–682, 1982. 4. Banerjee, S. D., R. H. Cohn, and M. R. Bernfield. Basal lamina of embryonic salivary epithelia. Production by the epithelium and role in maintaining lobular morphology. J. Cell Biol. 73: 445–463, 1977. 5. Barondes, S. H., D. N. W. Cooper, M. A. Gitt, and H. Leffler. Galectins: structure and function of a large family of animal lectins. J. Biol. Chem. 269: 20807–20810, 1994. 6. Bernfield, M., S. Banerjee, J. E. Koda, and A. C. Rapraeger. Remodeling of the basement membrane: morphogenesis and maturation. Ciba Found. Symp. 108: 179–196, 1984. 7. Bernfield, M., M. T. Hinkes, and R. L. Gallo. Developmental expression of the syndecans: possible function and regulation. Development Suppl.: 205–212, 1993.
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