REVIEW |
Correspondence to: John R. Couchman, Dept. of Cell Biology and Cell Adhesion and Matrix Res. Center, U. of Alabama at Birmingham, 1670 University Blvd., VH 201C, Birmingham, AL 35294-0019. E-mail: jrcouchman@cellbio.bhs.uab.edu
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Summary |
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At the epithelial/mesenchymal interface of most tissues lies the basement membrane (BM). These thin sheets of highly specialized extracellular matrix vary in composition in a tissue-specific manner, and during development and repair. For about two decades it has been apparent that all BMs contain laminins, entactin-1/nidogen-1, Type IV collagen, and proteoglycans. However, within the past few years this complexity has increased as new components are described. The entactin/nidogen (E/N) family has expanded with the recent description of a new isoform, E/N-2/osteonidogen. Agrin and Type XVIII collagen have been reclassified as heparan sulfate proteoglycans (HSPGs), expanding the repertoire of HSPGs in the BM. The laminin family has become more diverse as new -chains have been characterized, increasing the number of laminin isoforms. Interactions between BM components are now appreciated to be regulated through multiple, mostly domain-specific mechanisms. Understanding the functions of individual BM components and their assembly into macromolecular complexes is a considerable challenge that may increase as further BM and cell surface ligands are discovered for these proteins.
(J Histochem Cytochem 48:12911306, 2000)
Key Words:
basement membrane, entactin, nidogen, proteoglycan, agrin, collagen XVIII, laminin -chain
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Introduction |
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BASEMENT MEMBRANES (BMs) are thin sheets of highly specialized extracellular matrix (ECM) present at the epithelial/mesenchymal interface of most tissues, and which surround muscle, peripheral nerve fibers, and fat cells. Originally believed to serve as a selective barrier and scaffold to which cells adhere, it has become evident that the individual components of the BM are regulators of biological activities such as cell growth, differentiation, and migration, and that they influence tissue development and repair (
A significant number of interactions contribute to the supramolecular assembly of BMs. The current BM model proposes two networks, one consisting of collagen Type IV and the second made up of multiple laminins, interconnected via entactin-1 (
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Entactin-2/Nidogen-2/Osteonidogen |
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During the early 1980s, two groups described a novel BM glycoprotein now known as entactin or nidogen. Entactin-1/Nidogen-1 was initially isolated from murine EHS tumor and cell cultures (
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Mouse E/N-2 has only 27% amino acid similarity compared to mouse E/N-1, whereas human E/N-2 shares 46% amino acid similarity with human E/N-1. The human sequence of nidogen-2 is identical to osteonidogen except for 121 amino acid positions at the amino terminus (
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Recombinant human E/N-2 expressed in EBNA-293 cells was purified by metal chelation chromatography and yielded a major polypeptide of 200 kD, with a smaller one of 170 kD by SDS-PAGE electrophoresis (
Structural motifs are conserved between E/N-1 and E/N-2. The E/N-2 G2 domain contains EGF repeats 1 and 2 at its N-terminal, but with four additional EGF-like motifs in the rod domain. The G3 domain contains an EGF precursor/LDL receptor-homology region, and there are consensus sequences for calcium binding within the third and fifth EGF-like motifs. Differences between E/N-1 and E/N-2 include the presence of two thyroglobulin-like motifs in the rod domain of E/N-2 as opposed to one found in E/N-1. E/N-1 has an additional EGF-like motif at the carboxy terminal and two additional potential calcium binding sites at its amino terminal.
E/N-2 is as widespread as E/N-1. Northern blot analysis showed strong expression of E/N-2 transcript in heart, lung, skeletal muscle, kidney, liver, and testis, with lower levels in the brain and spleen, very similar to E/N-1. E/N-1 transcripts were more abundant than those of E/N-2 in liver, lung, and pancreas (
Double immunofluoresence microscopy revealed co-localization in kidney, skin, and testis. More specifically, in kidney both E/N isoforms were mainly localized in the BM zones of proximal and distal tubuli, glomeruli, and Bowman's capsule. Co-localization was also seen in skin, including the dermalepidermal junction, and in BMs of appendages and vessels of the dermis. In the testis, staining was present around seminiferous tubules and in deposits around Leydig cells. Two tissues in which co-localization did not occur were cardiac and skeletal muscle. E/N-1 staining was found around cardiocytes in the endomysium and perimysium and around blood vessels and nerve bundles. E/N-2 was equally prominent around vessels and nerves but was considerably weaker in the BM surrounding cardiocytes and myotubes (
To address this, Timpl and colleagues evaluated the proteinprotein interactions of the two E/N isoforms (1III3-5, possessing the only high-affinity binding site for E/N-1. Deletion of the E/N-1-binding module in recombinant
1III3-5 abolished binding of both E/N-1 and E/N-2, indicating that both proteins were interacting with the same region. However, when laminin-1 was saturated with E/N-1, E/N-2 was still able to bind, indicating a second site for E/N-2 interaction. E/N-2 bound collagen Types I and IV, as well as perlecan, with the same affinity as E/N-1, indicating that these binding sites are conserved between the two proteins. In contrast, E/N-2 was unable to bind fibulin-1 and -2 or tropoelastin (
Both mouse isoforms have an RGD sequence present in their rod domains suggestive of interactions with integrins. It occurs within the second EGF-like repeat of E/N-1 and the fifth EGF-like repeat of E/N-2. However, human E/N-2 has a YGD motif that may not be active in cell adhesion. E/N-1 and E/N-2 differ in cell adhesion properties (3 integrins; these reagents do block adhesion to E/N-1. Therefore, the data indicate that different integrins and/or non-integrin receptors are involved in cell adhesion to the two isoforms. These differences also suggest that the two isoforms have separate roles. Specific and redundant roles of these isoforms in BM architecture and function remain to be elucidated, and gene ablation studies in mice are eagerly awaited.
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Basement Membrane Proteoglycans: Agrin, Type XVIII Collagen, and Leprecan |
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The presence of BM proteoglycans was originally indicated in the kidney glomerulus by regular arrays of polyanionic binding sites for ruthenium red and cationized ferritin, as well as their sensitivity to heparitinase and nitrous acid (
Agrin
McMahan and colleagues first identified agrin as a 150-kD polypeptide found in extracts of Torpedo electric organ (
Signals that regulate muscle contraction, as well as some other aspects of muscle function, are conveyed from moto neurons to muscle at the neuromuscular junction (NMJ). Nerve-derived agrin is crucial for NMJ organization because of its ability to induce clustering of AChRs with postsynaptic membranes. AChRs regulate the electrical activity and contractile state of the muscle (
Neural HSPGs have been implicated in the stimulation of neurite outgrowth during development. HSPG binding to the neural cell adhesion molecule (NCAM) is required for NCAM-meditated cell adhesion (
Human agrin has been mapped to chromosome 1pter and mouse chromosome 4 (
There are six GAG attachment site consensus sequences, SGXG, in chick agrin cDNA (Fig 3). These regions contain additional SG sequences that are preceded or followed by acidic amino acids, which are conducive to HS addition (
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Agrin expression is widespread. A dot-blot evaluating mRNA levels in human tissues shows agrin to be most prominent in the adult kidney, lung, liver, and thyroid gland, with low amounts detected in all other tissues. Fetal tissues had low levels in all tissues tested, with most seen in the kidney and lung (3-,
4-, and
5-chains of collagen Type IV and laminin ß2-chain, whereas most other BMs express collagen Type IV
1- and
2-chains. In the lung, agrin was evident at the alveolar and capillary BM, and its function in the alveolar BM could be related to the follistatin repeats that are linked to protease inhibition (
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Alternate splicing of the transcript, yielding differentially spliced forms of agrin core protein, is tissue-specific (
Further insight into agrin's functions may be implied from agrin interacting or binding proteins. The amino terminal binds the coiled-coil region of laminin-1 (-dystroglycan (
-dystroglycan as an agrin receptor remains unclear. Furthermore, the clustering activity of agrin has been mapped to the carboxy terminal. Other putative agrin receptors include heparin binding growth association molecule (HB-GAM) (
vß1 (
Collagen XVIII
By definition, all collagenous polypeptides possess at least one sequence of a repeated Gly-X-Y motif; this motif allows three polypeptides to fold into triple-helical domains which are rigid and inextensible. In fibrillar collagens, the triple-helical domains polymerize in a staggered fashion to form fibrils. Collagens classified as fibrillar contain a long, uninterrupted stretch of Gly-X-Y repeats; these include collagen Types I, II, III, V, and XI. Nonfibrillar collagens have interruptions within the Gly-X-Y motif, creating regions of flexibility and thus interfering with their ability to form fibrils. These include Types IV, VI, VII-X, and XIIXIX. The most recently described subfamily of nonfibrillar collagens are the multiplexins, for proteins with multiple triple-helix domains and interruptions (
In addition to multiple genes, multiple promoters, and alternative splicing, which provides heterogeneity in collagens, there are also post-translational modifications, including glycanation. Types IX and XII are two members of the collagen family that are part-time proteoglycans, sometimes having GAG side chains. In this case, the GAGs attached to each of these collagens are chondroitin sulfate (
The collagen 1 (XVIII) cDNA sequence contains an open reading frame of 3420 bp, including ten triple-helical (COL) domains, varying in length, separated by 11 non-collagenous (NC) regions. The two terminal NC regions, NC11 at the amino terminal and NC1 at the carboxy terminal, are approximately 300 residues in length, whereas the other NC regions are only 1024 residues in length. Northern blot analyses indicate multiple RNA species and an abundance of message in kidney and liver. The human sequence was published in 1994 and showed 81.6% identity with that of the mouse (
1(XVIII) collagen gene was characterized and localized to chromosome 10 for mouse and 21q22.3 for human (
Type XVIII collagen has a region of homology with a large heparin binding amino-terminal portion of thrombospondin-1, a multifunctional glycoprotein with affinity for several molecules. This domain has also been identified in collagens V, IX, XI, and the large amino termini of collagens XII and XIV. However, the sequences believed to be involved in heparin binding are not conserved in the collagens. Therefore, the significance of the thrombospondin homology is unknown (
Some Gly-X-Y motifs of the collagenous domains are incomplete, and this is reminiscent of three other collagen chains 1 (XV),
1(XVI), and
1(XVII) (
1(XVIII) collagen chain is most similar to the
1 (XV) chain both in the lengths of some carboxy terminal triple-helical domains and the NC1 of collagen XVIII [60% amino acid identity of mouse Type XVIII with the human
1 (XV) chain], with conservation of the four cysteine residues (
Since the initial publications, both mouse and human collagen XVIII have been shown to have more than one variant; three are reported in mice and two in human (
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Several Ser-Gly dipeptides suitable for GAG attachment are found in the collagen XVIII sequence, raising the suspicion that collagen XVIII was a PG. When the protein was digested with chondroitinase to remove CS/DS GAGs, however, there was no change in the electrophoretic mobility of the protein (
Western blotting analysis of the vitreous body extracts showed a smear of 300 kD, the heterogeneity typical of a proteoglycan (
Collagen XVIII is of particular interest because of a 22-kD anti-angiogenic peptide with tumor-suppressing activity, known as endostatin, within its C terminal (50 residues); a central protease-sensitive hinge region (
70 residues); and a C-terminal endostatin domain (
180 residues;
Immunohistology of embryonic tissues localized endostatin to many but not all blood vessels and to some other BM zones. Immnunoelectron microscopy revealed a strong association of endostatin with elastic fibers of arteries. In addition, there was a distinct co-localization of endostatin with fibulin-1, fibulin-2, and nidogen-2, which correlated with in vitro binding studies (
The obvious growth of the BM HSPG family is under way, as is the family of BM chondroitin sulfate PGs (CSPGs). Surprisingly, perlecan can be included in this family because it can be secreted in some tissue and cell lines in culture with CS GAG substitution (
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New Additions to the Laminin Family |
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Laminin was first described as a component in the stroma of the EHS tumor (, ß, and
, respectively (
-chain polypeptide has a mass
400 kD; the smaller ß- and
-chains are both
200 kD (
-chain specific antibodies was widespread. However, laminin
1-chain was reported to be absent or low in adult and embryonic tissues (
1 chain (
1 in some BMs led to the possibility of other
-chains and additional laminin isoforms. To date, six
-, three ß-, and three
-laminin polypeptides have been described. Interestingly,
1 is found in complexes with each of the
-chains, which explains why antibodies against
1 stained all BMs, leading to the erroneous impression that there was perhaps just a single laminin trimer, as found in the EHS tumor. Thus far, there is evidence of 12 different laminin isoforms in vivo (
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The multiplicity of laminin isoforms provides for heterogeneity among BMs. The laminin family plays essential roles in structural integrity, cell adhesion, and signaling (1 null mice are embryonically lethal; there is no survival beyond 5.5 days post coitum due to the lack of BM establishment and failure of parietal yolk sac development. Embryoid bodies from
1 null cultured ES cells lacked BMs and produced disorganized extracellular deposits of collagen Type IV and perlecan. Entactin-1 and laminin
1-chain were secreted but did not become extracellular matrix-associated. Furthermore, the cells failed to differentiate into stable myotubes. The laminin
1 subunit is therefore necessary for laminin assembly and organization of BM components (
5 (
3,5/lam A chain, the precursor of vertebrate
3 and
5 chains, is embryonically lethal, with visible defects in mesoderm-derived tissue (
1,2-chain, the precursor of vertebrate
1- and
2-chains, is essential for embryonic viability and is involved in processes that require cell migration and cell adhesion (
The most recently described BM laminin isoforms are laminins 811 ( subfamily is comprised of six mammalian and two Drosophila members. The discovery of the
4 (
5 (
4ß1
1), -9 (
4ß2
1), -10 (
5ß1
1), and -11 (
5ß2
1). Laminin
-chains vary in size; the
1 (
400 kD),
2,
3b (
360 kD) (
5 (
450 kD) chains are full-length chains,
5 being the largest, whereas the
3a and
4 (
180 kD) chains are considered as truncated chains (Fig 6). Interactions of cells with laminin
-chains are critical for cellmatrix interactions. At least seven distinct integrin heterodimers (
1ß1,
2ß1,
3ß1,
6ß1,
7ß1,
9ß1,
6ß4, and
vß3) as well as dystroglycan, HSPGs, and HNK-1/L2 bind to sites on laminin
-chains (
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The laminin -chain genes are all expressed in both mouse embryos and adults, but in distinct spatiotemporal patterns. All chains are localized to the ECM and, with a few exceptions, more specifically to BMs. All BMs studied to date contain at least one
-chain, and many BMs have more than one
-chain subfamily member. Contrary to early reports, the
1 laminin chain has the most restricted distribution, whereas the
5 laminin chain is the most widely distributed
-chain in adult vertebrates (
-chain expression are established embryonically, but some individual BMs switch
-chains as development proceeds; this sort of switching has been detailed for kidney development (
Here we focus on the most recently described members of the -chain subfamily,
4 and
5. These
-chains are more widely expressed than the
1-,
2-, and
3-chains.
5 expression in murine development; it was present in most embryonic and extraembryonic BMs at early stages but became restricted to a distinct subset of BMs as development proceeded. The
5-chain localized to practically all
1-positive BMs at E8.5, including BMs underlying the neural folds and the surface ectoderm as well as BMs associated with gut epithelium. The
5-chain was also a prominent component of BMs around somites. In later stages of development,
5 was expressed in a subset of BMs and remained abundant in the surface ectodermal BM throughout embryogenesis.
Ribonuclease protection analysis of various E17.5 and adult mouse tissues revealed that low to moderate levels of 4 and abundant levels of
5 RNA were present in all tissues tested, with lowest expression in the liver for both. In situ hybridization performed on E15.5 day embryos revealed that laminin
4 was expressed strongly in mesenchymal tissues of the head, dorsal root ganglia, and intestine, and was observed diffusely in skeletal and cardiac muscle. Laminin
5 was strongly expressed in skin, lung, olfactory epithelium, the superficial layers of the tongue and palate, salivary gland, intestine, and the most superficial cells of the liver (
Analysis of protein expression and localization was carried out using polyclonal antibodies against the 4 and
5 laminin chains. In adult murine kidney,
4, although absent from all renal, epithelial, and arterial BMs, was found in many capillaries of the medulla. A more widespread expression was found for the
5-chain, for which virtually all BMs, including those of glomeruli, arteries and all tubules were positive.
4 expression in heart was restricted to capillaries and was found at low levels in many myocyte BMs (
5 localized to the arterioles and capillaries and was found at low levels in many myocyte BMs. The
5-chain co-localized with
3 in most alveolar BMs of the lung, whereas
4 was expressed in a subset of alveolar BMs (
4- and
5-chains co-localized with the either the ß1- or the ß2-chain and the
1-chain. Expression patterns of isoforms containing
4 and
5, as well as other laminin isoforms, in the peripheral nervous system and the spinal cord are reviewed by
5 has a widespread distribution in adult tissues and might replace
1 either in endothelium or in epithelium, which lack
1.
Because of its widespread distribution, it was not surprising that mice null for the 5 laminin chain result in fetal lethality (
5-chain, including limb, neural tube, placenta, lung, heart, intestine, and kidney. More specifically, the kidneys were either small or absent and had defective glomerulogenesis (
5 may be important in placental endothelial cell migration and blood vessel branching, trophoblast adhesion to BM, and BM formation. In addition to the roles suggested by the
5 null mice,
5 is an early molecular marker for sexual differentiation and is regulated by the testis-determining factors (
5-chain, defective matrix assembly was observed. It will be interesting to see whether the deletion of the
4-chain gene will have a milder phenotype based on its restricted distribution.
Laminin chains are not always localized to the BM. This is evidenced by the recent description of the 3-chain (
3-chain as being generally expressed in endothelial cells of arterioles and capillaries as well as interstitial cells of certain tissues. Alternatively,
3-chain was localized within the BM of the dermalepidermal junction at points of nerve penetration. The chain was also prominent along the apical surface of ciliated epithelial cells of lung, oviduct, epididymis, ductus deferens, and seminiferous tubules. This distribution of
3-containing laminins on the apical surfaces of a variety of epithelial tissues is novel and suggests the possibility that apical laminins are important in morphogenesis and structural stability of the cilitated processes of these cells (
3 is complexed to
2 and ß1 laminin chains, and therefore represents the twelfth laminin isoform described (
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Summary |
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Basement membranes are far more complex than conventional electron microscopy originally led us to believe. The proteins discussed above illustrate the heterogeneous complexity of BM structure and function. Tissue specific BMs, in terms of composition, are now revealed, as are further roles for their components. Further complexity is likely to arise as the human genome project is completed and further BM proteins are discovered. These discoveries are only a prelude to the vast amount of work that lies ahead. Interactions among other BM proteins will have to be elucidated, as well as potential cell surface receptors. Post-translational modifications are many and varied. It is not clear why there are multiple HSPGs in BMs. Pehaps there are core protein-specific glycanation events that yield HS chains with specific fine structure and binding attributes. Multiple collagens can be glycanated, but the reasons are not clear. Normal functions of these proteins in vivo may offer insight into many inherited and acquired BM-associated diseases and, perhaps, future prospects for gene therapy.
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Acknowledgments |
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Supported in part by National Institutues of Health grant RO1 AR36457 to Dr J.R. Couchman.
We thank Dr G.J. Cole (Ohio State University) for the gift of the agrin antibody.
Received for publication March 27, 2000; accepted June 29, 2000.
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