The Basement Membrane/Basal Lamina of Skeletal Muscle

basement membrane basal lamina acetylcholinesterase acetylcholine receptor muscle-specific kinase Many cells, including skeletal muscle fibers, are coated by a layer of extracellular matrix material called the basement membrane (BM).1 The BM, in turn, is composed of two layers: an internal, felt-like basal lamina (BL) directly linked to the plasma membrane, and an external, fibrillar reticular lamina. BMs contain protein and carbohydrate but no lipid or nucleic acid. Virtually all the protein is glycosylated, and nearly all the carbohydrate is covalently bound to protein. The fibrils of the reticular lamina are collagenous, and they are embedded in an amorphous proteoglycan-rich ground substance. The BL contains non-fibrillar collagen, non-collagenous glycoproteins, and proteoglycans (1Timpl, R., and Rohrbach, O. (eds) Molecular and Cellular Aspects of Basement Membranes, Academic Press, New York.Google Scholar). Initially, the BM was viewed as a static structure that provides mechanical support; essentially something for the cells to sit on. A key advance was the discovery that, because the acellular BM survives injury to associated cells, it can provide a scaffold to orient and constrain cells during regeneration (2Vracko R. Benditt E.P. J. Cell Biol. 1972; 55: 406-419Crossref PubMed Scopus (276) Google Scholar). A more radical transformation over the past few decades was the realization that BM components play active roles and that these roles extend to developmental as well as regenerative processes (1Timpl, R., and Rohrbach, O. (eds) Molecular and Cellular Aspects of Basement Membranes, Academic Press, New York.Google Scholar). In skeletal muscle, these processes include myogenesis and synaptogenesis. Most recently, emphasis has shifted to a search for the matrix-associated signals and membrane-associated receptors that underlie cell-matrix interactions. The purpose of this minireview is to relate results from the new molecular analyses to the early cellular observations that motivated them. For more detailed descriptions of what happened in between, see Refs. 3Sanes J.R. Engel A.G. Franzini-Armstrong C. Mycology. McGraw Hill, New York1994: 242-260Google Scholar, 4Sanes J.R. Semin. Dev. Biol. 1995; 6: 163-173Crossref Scopus (28) Google Scholar, 5Sanes J.R. Lichtman J.W. Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1209) Google Scholar. Although we now know that BMs are present in nearly all tissues, their existence was first appreciated in muscle. In his 1840 report "On the Minute Structure and Movements of Voluntary Muscle," Bowman (6Bowman W. Philos. Trans. R. Soc. Lond. Biol. Sci. 1840; 130: 457-494Crossref Google Scholar) described a "highly delicate, transparent, and probably elastic" sheath encircling individual muscle fibers. This sheath, which he called the sarcolemma, became apparent when muscle fibers were injured during dissection; the cell itself lysed and retracted, leaving the sarcolemma behind (Fig.1). Over a century later, electron microscopy revealed that the BM is the main component of such tubes and that the BL is a main component of the BM. Today the term sarcolemma is often used to refer to the plasma membrane alone, although only fragments of it were present in Bowman's tubes (3Sanes J.R. Engel A.G. Franzini-Armstrong C. Mycology. McGraw Hill, New York1994: 242-260Google Scholar). The terms BL and BM are often used interchangeably, but should not be; I will attempt to use them appropriately here. Bowman's view of what we now know to be BM and particularly his evidence for its "strength and tenacity" (6Bowman W. Philos. Trans. R. Soc. Lond. Biol. Sci. 1840; 130: 457-494Crossref Google Scholar) led directly to appreciation of its role in muscle function. Muscles are strong, flexible, and stress-resistant. Formal models of their mechanical properties include both contractile and elastic elements. The contractile element is, of course, the sarcomere, and extracellular matrix accounts for much of the elasticity. In fact, several matrix-rich structures contribute to muscle strength and elasticity, but a sizable fraction has been shown to reside in the BM (7Tidball J.G. Biophys. J. 1986; 50: 1127-1138Abstract Full Text PDF PubMed Scopus (35) Google Scholar). Direct biophysical analysis of BM is lacking, but keys to its strength most likely are its major structural components (8Timpl R. Brown J.C. Bioessays. 1996; 18: 123-132Crossref PubMed Scopus (575) Google Scholar, 9Colognato H. Yurchenco P.D. Dev. Dyn. 2000; 218: 213-234Crossref PubMed Scopus (1024) Google Scholar). The most abundant protein of the BL is triple-helical collagen IV, the subunits of which, called α chains, have prominent terminal non-collagenous domains. The major non-collagenous protein is laminin, which is also a heterotrimer of related chains, in this case called α, β, and γ. Both collagens IV and laminins exist in multiple isoforms, with the most abundant in muscle being collagen (α1(IV))2(α2(IV))1 and laminin α2β1γ1 (also called laminin-2). The basic structure of BLs appears to involve distinct networks of collagens IV and laminin, each of which is capable of self-assembly. The collagen network becomes cemented by covalent cross-links, and the two networks are linked to each other by another non-collagenous glycoprotein, entactin/nidogen. These core components bear a multitude of recognition sites that bind other BL components, anchor reticular lamina components to the BL, and serve as ligands for membrane-associated receptors. Among the transmembrane receptors are the integrins and dystroglycans, both of which interact with the cytoskeleton (10Michele D.E. Campbell K.P. J. Biol. Chem. 2003; 278 (January 29, 10.1074/jbc.R200031200)Abstract Full Text Full Text PDF Scopus (366) Google Scholar, 11Mayer U.R. J. Biol. Chem. 2003; 278: 14587-14590Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Thus, one can envision a series of direct linkages that together span the distance from reticular lamina to BL to plasma membrane to cytoskeleton. The BM provides a significant fraction of the tensile strength of the whole structure (3Sanes J.R. Engel A.G. Franzini-Armstrong C. Mycology. McGraw Hill, New York1994: 242-260Google Scholar), presumably via the collagen/laminin networks of BL, which run orthogonal to this axis. Genetic studies of muscle disease show that the BM is critical for the maintenance of muscle integrity. Positional cloning in humans and analysis of naturally occurring and targeted mutants in mice have revealed that muscular dystrophy can arise from loss of any of several components in the reticular lamina-BL-membrane-cytoskeleton linkage. These include laminin α2 (congenital muscular dystrophy), its major transemembrane receptors, integrin α7 and dystroglycan; dystrophin, which links dystroglycan to the cytoskeleton (Duchenne muscular dystrophy); the dystroglycan- and dystrophin-associated sarcoglycans (limb-girdle muscular dystrophies); and the α chains of collagen VI, which help connect the BL to the reticular lamina (Bethlem myopathy) (10Michele D.E. Campbell K.P. J. Biol. Chem. 2003; 278 (January 29, 10.1074/jbc.R200031200)Abstract Full Text Full Text PDF Scopus (366) Google Scholar, 11Mayer U.R. J. Biol. Chem. 2003; 278: 14587-14590Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 12Helbling-Leclerc A. Zhang X. Topaloglu H. Cruaud C. Tesson F. Weissenbach J. Tome F.M. Schwartz K. Fardeau M. Tryggvason K. et al.Nat. Genet. 1995; 11: 216-218Crossref PubMed Scopus (558) Google Scholar, 13Xu H. Wu X.R. Wewer U.M. Engvall E. Nat. Genet. 1994; 8: 297-302Crossref PubMed Scopus (320) Google Scholar, 14Blake D.J. Weir A. Newey S.E. Davies K.E. Physiol. Rev. 2002; 82: 291-329Crossref PubMed Scopus (886) Google Scholar, 15Jobsis G.J. Keizers H. Vreijling J.P. de Visser M. Speer M.C. Wolterman R.A. Baas F. Bolhuis P.A. Nat. Genet. 1996; 14: 113-115Crossref PubMed Scopus (215) Google Scholar). Importantly, in all of these diseases, muscles develop normally but then degenerate. Thus, even though the BL does play roles in myogenesis (see below) it is separately required for muscle maintenance. In part, this requirement may be a passive, mechanical one, but more active mechanisms also contribute. The core BL components, laminin and collagen IV, are signaling as well as structural molecules, and their receptors, dystroglycan and integrins, are signal transducers. For example, active signaling from laminin α2 may provide a survival signal for muscle, and its absence in congenital dystrophy is associated with particularly high levels of apoptosis (16Vachon P.H. Loechel F. Xu H. Wewer U.M. Engvall E. J. Cell Biol. 1996; 134: 1483-1497Crossref PubMed Scopus (193) Google Scholar). In short, muscle maintenance requires both the structural and signaling properties of BL. In one of the first clear demonstrations that extracellular matrix influences cellular differentiation, Hauschka and Konigsberg (17Hauschka S.D. Konigsberg I.R. Proc. Natl. Acad. Sci. U. S. A. 1966; 55: 119-126Crossref PubMed Scopus (332) Google Scholar) showed that substrate-bound collagen could replace "conditioned medium" factors in promoting the formation of myotubes from cultured myoblasts. Subsequent work showed that several matrix components affect myogenesis. Of these, laminin appears to be particularly critical. Laminin enhances proliferation of myoblasts, stimulates their motility, and leads them to assume the bipolar shape characteristic of fusing cells (18Foster R.F. Thompson J.M. Kaufman S.J. Dev. Biol. 1987; 122: 11-20Crossref PubMed Scopus (133) Google Scholar). Myotube formation is decreased, although not abolished, in the absence of laminin (19Smyth N. Vatansever H.S. Murray P. Meyer M. Frie C. Paulsson M. Edgar D. J. Cell Biol. 1999; 144: 151-160Crossref PubMed Scopus (408) Google Scholar). In contrast, fibronectin selectively promotes adhesion of fibroblasts and may lead to dedifferentiation of myoblasts (20von der Mark K. Ocalan M. Differentiation. 1989; 40: 150-157Crossref PubMed Scopus (108) Google Scholar). The locations of these proteins also differ; laminin adjoins myotubes whereas fibronectin is initially excluded from myogenic regions (20von der Mark K. Ocalan M. Differentiation. 1989; 40: 150-157Crossref PubMed Scopus (108) Google Scholar). Therefore, laminin and fibronectin may be involved in sorting myoblasts from fibroblasts as well as in orchestrating their differentiation. In addition, laminin and collagen IV provide binding sites for proteoglycans, the principal one in muscle being perlecan (8Timpl R. Brown J.C. Bioessays. 1996; 18: 123-132Crossref PubMed Scopus (575) Google Scholar). The glycosaminoglycan chains of the proteoglycans, in turn, provide binding sites that concentrate and present bioactive polypeptides such as fibroblast growth factors and transforming growth factors, which are critical for myogenesis (21Pirskanen A. Kiefer J.C. Hauschka S.D. Dev. Biol. 2000; 224: 189-203Crossref PubMed Scopus (57) Google Scholar, 22Baeg G.H. Perrimon N. Curr. Opin. Cell Biol. 2000; 12: 575-580Crossref PubMed Scopus (94) Google Scholar). Indeed, these nominally soluble factors are predominantly matrix-associated in vivo. Thus, major BL components not only promote myogenesis directly but also orchestrate muscle development by presentation of morphogenic, mitogenic, and trophic factors. Bowman's discovery of the BM arose from its persistence following injury during dissection. When injury occurs in vivo, new muscle fibers regenerate from a resident population of stem cells, called satellite cells, which are wedged between muscle fiber and BL. Bowman (6Bowman W. Philos. Trans. R. Soc. Lond. Biol. Sci. 1840; 130: 457-494Crossref Google Scholar) noted that the BM "provides an effectual barrier between the parts within and those without"; as predicted from this property, most satellite cells remain within the BL as they divide and form myotubes (2Vracko R. Benditt E.P. J. Cell Biol. 1972; 55: 406-419Crossref PubMed Scopus (276) Google Scholar, 23Sanes J.R. Marshall L.M. McMahan U.J. J. Cell Biol. 1978; 78: 176-198Crossref PubMed Scopus (397) Google Scholar). Thus, by constraining the growth and migration of activated satellite cells, BL orients the regeneration of new muscle fibers. From what we know about myogenesis, it seems likely that the BL also actively promotes regeneration. In addition, BL acts as a mechanical barrier to prevent migratory loss of satellite cells from normal muscle and could be involved in repressing satellite cell mitosis and differentiation in the absence of damage. The guidance that BL provides is of functional importance. Muscles do regenerate if the BL is disrupted, but myotubes are not oriented in parallel so the regenerate as a whole may develop little net force (3Sanes J.R. Engel A.G. Franzini-Armstrong C. Mycology. McGraw Hill, New York1994: 242-260Google Scholar). Furthermore, because BLs of nerves and blood vessels also act as scaffolds for regeneration (2Vracko R. Benditt E.P. J. Cell Biol. 1972; 55: 406-419Crossref PubMed Scopus (276) Google Scholar, 24Nguyen Q.T. Sanes J.R. Lichtman J.W. Nat. Neurosci. 2002; 5: 861-867Crossref PubMed Scopus (242) Google Scholar), the integrity of connective tissue favors rapid revascularization and reinnervation. In general, recovery of function is good following injuries that minimally disrupt the integrity and orientation of the sheaths and poor following injuries that destroy these scaffolds. The extracellular matrix is structurally and functionally specialized in areas where muscle abuts tendon or nerve. At the neuromuscular junction, BL but not reticular lamina passes between nerve and muscle membranes and extends into junctional folds that invaginate the postsynaptic membrane (Fig.2). The BL thus constitutes a sizable fraction of the synaptic cleft material of the neuromuscular junction. The cleft is 50-nm-wide, which is a greater distance than that spanned by membrane-associated adhesion molecules (e.g. cadherins). Based on these considerations alone, it is evident that the BL must contribute to the tight adhesion of pre- and postsynaptic partners. Indeed, when muscles are treated with proteases that digest BL but not plasma membrane, nerve terminals lose their firm attachment to the end plate and can easily be pulled away (25Betz W. Sakmann B. J. Physiol. (Lond.). 1973; 230: 673-688Crossref Scopus (118) Google Scholar). Moreover, when muscle is damaged but not denervated, nerve terminals remain at their original sites on the BL for months after the muscle fiber has degenerated (22Baeg G.H. Perrimon N. Curr. Opin. Cell Biol. 2000; 12: 575-580Crossref PubMed Scopus (94) Google Scholar,26Dunaevsky A. Connor E.A. Dev. Biol. 1998; 194: 61-71Crossref PubMed Scopus (17) Google Scholar). Adhesion is likely to be mediated in part by integrins and dystroglycan (27Cohen M.W. Hoffstrom B.G. DeSimone D.W. J. Neurosci. 2000; 20: 4912-4921Crossref PubMed Google Scholar, 28Martin P.T. Kaufman S.J. Kramer R.H. Sanes J.R. Dev. Biol. 1996; 174: 125-139Crossref PubMed Scopus (152) Google Scholar). Other potential adhesive systems are mentioned below. At the myotendinous junction, the surface of the muscle fiber is thrown into invaginations that resemble junctional folds but are deeper. BL extends into these invaginations and is attached to the plasma membrane by periodically arrayed microfibrils (29Benjamin M. Ralphs J.R. Int. Rev. Cytol. 2000; 196: 85-130Crossref PubMed Google Scholar). These fibrils and the increased area of membrane-matrix apposition provided by the invaginations are adaptations for the transmission of force from muscle to tendon. Some molecular differences have been noted between the BL at the myotendinous junction and that coating adjoining regions of the sarcolemma (30Patton B.L. Microsc. Res. Tech. 2000; 51: 247-261Crossref PubMed Scopus (80) Google Scholar, 31Pedrosa-Domellof F. Tiger C.F. Virtanen I. Thornell L.E. Gullberg D. J. Histochem. Cytochem. 2000; 48: 201-210Crossref PubMed Scopus (23) Google Scholar), but the functional significance of these differences is unknown. The key events in neuromuscular transmission are release of acetylcholine from the nerve terminal and activation of acetylcholine receptors in the postsynaptic membrane. One might that the BL of acetylcholine the synaptic but studies show that its to receptors is Proc. Natl. Acad. Sci. U. S. A. PubMed Google Scholar). This is with from analysis of BL in which is an only for K. J. Curr. Opin. PubMed Scopus Google Scholar). Thus, of to receptors and the components of its are not by BL. the other the BL is involved in the of acetylcholine by acetylcholinesterase which than by was initially that was attached to the membrane, as is the case in Subsequent studies that a major fraction of at the neuromuscular is associated with synaptic BL Nat. New Biol. PubMed Scopus Google Scholar, U.J. Sanes J.R. Marshall L.M. 1978; PubMed Scopus Google Scholar). The key to the is a that is to of much of the synaptic in muscle but little in is associated with the U.J. Sanes J.R. Marshall L.M. 1978; PubMed Scopus Google Scholar). The molecular analysis recently, but its is for has now been and J. 2002; 11: PubMed Scopus Google Scholar, E. S. N. C. J. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the in mice leads to loss of synaptic and of in humans underlie of congenital E. J. J.M. J. Sanes J.R. J. Cell Biol. 1999; 144: PubMed Scopus Google Scholar, A. K. J. S. I. Engel A.G. 2002; PubMed Scopus Google Scholar). in turn, to perlecan in the BL H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, E. Nat. Neurosci. 2002; 5: PubMed Scopus Google Scholar). is a to the of the that loss of or is but not whereas of by nerve leads to nerve regenerate to form new neuromuscular Over S. and of the Press, New Scholar) that the show a for original synaptic Indeed, when to nerve and muscle are over of the by on muscle fibers at original even though these sites only about of the muscle fiber surface J.R. Lichtman J.W. Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1209) Google Scholar). Some of this of the connective tissue that been associated with the original a in which the nerve BL a prominent role Q.T. Sanes J.R. Lichtman J.W. Nat. Neurosci. 2002; 5: 861-867Crossref PubMed Scopus (242) Google Scholar). the muscle fibers, they original sites at a of the existence of recognition factors associated with the muscle fiber on injured muscle showed that of these factors are associated with when muscles were denervated, and then to prevent muscle original synaptic sites on the BL sheaths J.R. Marshall L.M. McMahan U.J. J. Cell Biol. 1978; 78: 176-198Crossref PubMed Scopus (397) Google Scholar). Based in part on this several for BL components selectively associated with synaptic several have been including laminin and collagen IV proteoglycans, and growth factors in by proteoglycans (Fig.2). A few components, such as the collagen IV and α2 chains, are excluded from synaptic and a including and is present both and J.R. Semin. Dev. Biol. 1995; 6: 163-173Crossref Scopus (28) Google Scholar, B.L. Microsc. Res. Tech. 2000; 51: 247-261Crossref PubMed Scopus (80) Google J.R. J. Cell Biol. PubMed Scopus Google Scholar, J.R. 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Importantly, these only in the fraction of the that directly the postsynaptic that factors differentiation. of BL sheaths from which muscle fibers been (see also active and synaptic as well as the to when Moreover, new active in these terminals in with of BL that sites where junctional folds active been J.R. Marshall L.M. McMahan U.J. J. Cell Biol. 1978; 78: 176-198Crossref PubMed Scopus (397) Google Scholar). This showed that of differentiation were within the BL. Among the of differentiation are the synaptic The laminin was initially by of its in synaptic BL J.P. Sanes J.R. 1989; PubMed Scopus Google Scholar). are to to postsynaptic P.T. Sanes J.R. 1995; PubMed Scopus Google Scholar), to formation of a BL in which synaptic sites bear whereas regions are in Moreover, fragments or in to and to into nerve terminals J. Sanes J.R. 1995; 14: Full Text PDF PubMed Scopus Google Scholar, B.L. Sanes J.R. J. Neurosci. 1999; 11: PubMed Scopus (28) Google Scholar). This with the that these results a for the existence of multiple they functional synaptic in a structural In direct of this differentiation is at neuromuscular in few active release is decreased, cell processes the synaptic and of neuromuscular the of M. J. Sanes J.R. J.P. 1995; PubMed Scopus Google Scholar, B.L. Sanes J.R. 1998; PubMed Scopus Google Scholar). Thus, laminins as of differentiation. the other the that differentiation to a in the absence of that analysis of muscle laminins revealed the of α chains in synaptic BL and but only one B.L. Sanes J.R. J. Cell Biol. PubMed Scopus (366) Google Scholar). Thus, synaptic BL may contain and and all of which might be involved in differentiation. Genetic studies and analyses in distinct roles for each promotes differentiation and cell promotes the of pre- and postsynaptic and may be for structural as is (30Patton B.L. Microsc. Res. Tech. 2000; 51: 247-261Crossref PubMed Scopus (80) Google Scholar, B.L. Sanes J.R. J. Cell Biol. PubMed Scopus (366) Google Scholar, B.L. J.M. J. J. H. Tryggvason K. Sanes J.R. Nat. Neurosci. PubMed Scopus Google Scholar, J.P. P.A. Res. 1998; PubMed Scopus Google Scholar). Thus, of the to and differentiation. The distinct of synaptic laminins that they have multiple receptors on and presumably include integrins, which bind laminins integrin is at active (27Cohen M.W. Hoffstrom B.G. DeSimone D.W. J. Neurosci. 2000; 20: 4912-4921Crossref PubMed Google Scholar). In addition, and with distinct membrane components, the that release and the S.J. Sanes J.R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Sanes J.R. J. Neurosci. 2000; 20: PubMed Google Scholar). These the that laminins could differentiation in part by direct with critical components of the release receptors are in myotubes but in the postsynaptic membrane of muscle can on their but studies a of to postsynaptic including at sites of J.R. Lichtman J.W. Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1209) Google Scholar, J.R. Lichtman J.W. Nat. Rev. Neurosci. PubMed Scopus Google Scholar). synaptic are of associated with synaptic and BL components, at synaptic sites for following The of BL that it might play a role in postsynaptic and on BL sheaths this When myotubes in these following and (see new postsynaptic including in apposition to synaptic BL, even though the was S.J. McMahan U.J. J. Cell Biol. 82: PubMed Scopus Google Scholar). These results the that of the of postsynaptic differentiation might be in or by the BL. In fact, of postsynaptic only one has been shown to play a vivo, and this is a synaptic BL was by McMahan and U.J. Biol. Scopus Google Scholar) in a search for bioactive components of synaptic BL. is a with that interact with the muscle membrane and an that binding to laminin in the BL U.J. Biol. Scopus Google Scholar, F. C. R.H. 6: Full Text PDF PubMed Scopus Google Scholar, R. M. M. J. Cell Biol. PubMed Scopus Google Scholar). is by and into the synaptic cleft C. McMahan U.J. J. Cell Biol. 1987; PubMed Scopus Google Scholar). and studies the that is and for postsynaptic differentiation. of the in mice leads to in neuromuscular and of in muscle leads to of a postsynaptic I. M. McMahan U.J. Neurosci. PubMed Scopus Google Scholar, M. Sakmann B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M. F. R.H. J.P. Sanes J.R. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). A potential is that muscles as well as only the by of called are more active than at and targeted of the leads to postsynaptic as as those in the absence of all Q.T. Lichtman J.W. Sanes J.R. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a it is not that with cellular receptors, including the cell adhesion molecules, and integrins J.R. Lichtman J.W. Annu. Rev. Neurosci. 1999; 22: 389-442Crossref PubMed Scopus (1209) Google Scholar). Genetic analysis has that of these are required for the critical receptor of at for this is a receptor kinase called of in turn, leads to of with the cytoskeleton via a protein called J.R. Lichtman J.W. Nat. Rev. Neurosci. PubMed Scopus Google Scholar). binding the BL both the signal and its persistence by the nerve. In addition, dystroglycan and proteins associated with it are involved in the and maintenance of the postsynaptic membrane in J.R. Lichtman J.W. Nat. Rev. Neurosci. PubMed Scopus Google Scholar, M. S. Sanes J.R. Lichtman J.W. 2002; Full Text Full Text PDF PubMed Scopus Google it seems likely that the dystroglycan ligands in synaptic BL, and laminin, are involved in the of the The BL of skeletal muscle a of roles during development and in is in but all have been and molecular analysis is now well as one of the in which we are to relate the molecular of BL to its function. Some which may be to other tissues, are as The original view of the BL as a mechanical has been not by the realization that it also has and mediated by individual The major components of BL, laminins and collagens IV, are not only structural which form networks within BL and links to but they are also signaling molecules that receptors in the membrane. Both laminins and collagens IV are of molecules that cells can to within a BL. This provides a for of signals within a structural sites on the core BL components of abundant components such as The glycosaminoglycan components of the proteoglycans, in turn, and present nominally soluble signaling molecules, such as growth factors. the structural and roles of BL can be its to serve as a in which adjoining cells can that direct the differentiation and function of the