Basement Membranes: Cell Scaffoldings and Signaling Platforms

Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Basement Membranes: Cell Scaffoldings and Signaling Platforms Peter D. Yurchenco Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 Correspondence: [email protected] Basement membranes are widely distributed extracellular matrices that coat the basal aspect of epithelial and endothelial cells and surround muscle, fat, and Schwann cells. These extracellular matrices, first expressed in early embryogenesis, are self-assembled on competent cell surfaces through binding interactions among laminins, type IV collagens, nidogens, and proteoglycans. They form stabilizing extensions of the plasma membrane that provide cell adhesion and that act as solid-phase agonists. Basement membranes play a role in tissue and organ morphogenesis and help maintain function in the adult. Mutations ad- versely affecting expression of the different structural components are associated with developmental arrest at different stages as well as postnatal diseases of muscle, nerve, brain, eye, skin, vasculature, and kidney. he basement membrane (basal lamina)was ancient structures, likely appearing when or- Tfirst described in muscle as a “membran- ganized communities of animal cells first aceous sheath of the most exquisite delicacy” emerged. These matrices serve as an extension (Bowman 1840). Microscopists subsequently of the plasma membrane, protecting tissues identified basement membranes in nearly all from disruptive physical stresses, and provide tissues. In the late 1970s, the discovery of the an interactive interface between cell and sur- basement membrane-rich EHS tumor led to rounding environment that can mediate local the isolation of abundant quantities of laminin, and distant signals within and between these type IV collagen, nidogen (entactin), and perle- compartments. Such signals appear to be largely can, enabling elucidation of their biochemi- processed through integrins, growth factor cal and cell-interactive properties and opening interactions, and dystroglycan. Basement mem- a door to an understanding of structure and brane-dependent functions include the promo- function of basement membranes at a molecu- tion of strong epidermal/dermal attachment, lar level. stabilization of the skeletal muscle sarcolemma, Basement membranes are layered cell-ad- selectivity of glomerular filtration, and estab- herent extracellular matrices (ECMs) that form lishment of epithelial and glial cell polarization. part of tissue architecture, contributing both Assembly of a functionally active basement to embryonic differentiation and the mainte- membrane depends on the binding interac- nance of adult functions. They are evolutionarily tions among the large carbohydrate-modified Editors: Richard Hynes and Kenneth Yamada Additional Perspectives on Extracellular Matrix Biology available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004911 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004911 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press P.D. Yurchenco proteins, each consisting of an array of dis- differential developmental and tissue-specific tinct domains with unique binding properties. expression patterns.1 These components, in turn, are organized into By electron microscopy of glutaraldehyde- higher ordered supramolecular assemblies that fixed and heavy-metal-impregnated thin sec- engage cell surface receptors in a developmen- tions, the basement membrane is typically tally and tissue-specific manner. In this review seen as consisting of an electron-dense layer models of structure will be related to those of (lamina densa) separated from the plasma function based on a consideration of morpho- membrane by an electron-lucent layer (lamina logical, biochemical, cell biological, develop- lucida). However, the significance of this dis- mental, and genetic information. tinct morphology was brought into question by the technique of rapid freeze-substitution in which a homogenous ultrastructure was observed (Chan et al. 1993; Chan and Inoue SUPRAMOLECULAR ARCHITECTURE 1994; Miosge 2001). A detailed study of Reich- Each basement membrane contains at least one ert’s membrane revealed a three-dimensional member of the heterotrimeric laminin family, branching network of fine filaments and cords one or two nidogens, the heparan sulfate pro- (Inoue et al. 1983). By ultrathin high-angle plat- teoglycans (HSPGs) perlecan and/or agrin, and inum/carbon shadowing, the supramolecular one or more of the variants of type IV collagens organization was seen to consist of a branching (Fig. 1). We recognize these components as ma- network of type IV collagen containing end- jor contributors to the formation of the basic to-end and lateral associations and a mesh of architectural scaffolding and array of interactive short interconnecting struts corresponding to ligands. The laminin and collagen isoforms the laminin polymer in which the combined possess differences in their assembly, receptor- laminin/collagen network “pore” size was on binding, and/or subsequent cross-linking, al- the order of 10 nm (Yurchenco and Ruben lowing variations in final structure, signaling, 1987; Yurchenco et al. 1992). and stability. Laminins, type IV collagens, perlecan, and agrin are large macromolecules rang- ing from 75 nm to 400 nm in greatest BASEMENT MEMBRANE SELF-ASSEMBLY length. In typical thin basement membranes AND RECEPTOR INTERACTIONS (50–100 nm thick), the basic components are likely organized into a single molecular layer Basement membranes have been deduced to with the long axes of laminin and collagen par- assemble (Fig. 2) through a multistep process allel to the surface. In thicker basement mem- that is substantially mass action-driven (self- branes, such as those of Reichert’s membrane, assembly) and that is initiated by the binding the renal glomerulus, lens capsule, and EHS of laminins to competent (i.e., laminin-bind- tumor matrix, the interior basement mem- ing) cell surfaces (Smyth et al. 1998; Li et al. brane molecules reside beyond the reach of 2002; Li et al. 2005b; McKee et al. 2007; McKee receptors and interact only through intercom- et al. 2009). The intercomponent binding inter- ponent architectural bonds. Collagens type actions and polymerizations of laminins and XVIII, XV, and VI are found at the basement type IV collagen that create a relevant scaffold membrane/stromal interface and are thought matrix were first identified and characterized to mediate their attachment. Additionally, fi- by a study of purified components in vitro. As- bronectin, usherin, bamacan, nephronectin, sembly on cells, however, has been found to be papilin, netrins, and other components can be found within basement membranes, adding 1The reader should be aware of a comprehensive mouse additional receptor-binding activities (e.g., E16.5 expression reference map of the different basement membrane components, generated by K. Sekiguchi and col- nephronectin) and/or modulating structure leagues, to be found at the website http://www.matrixome. (e.g., netrin-4). All of the components show com/bm. 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004911 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Basement Membranes facilitated by anchorage to select cell surfaces general, the laminins differ from each other that serves to increase the local surface concen- on the basis of short arm domain composition, tration of components, promoting the interac- a-subunit LG integrin- and dystroglycan- tions (Kalb and Engel 1991; Li et al. 2005b; binding affinities/specificities, and posttrans- McKee et al. 2007). This initial anchoring inter- lational proteolytic processing of amino- and action appears to occur primarily through the carboxy-terminal globular domains. The a- laminin LG domains (Figs. 1–3) that can bind subunits are largely responsible for cell surface to sulfated glycolipids, integrins, dystroglycan, adhesion and receptor interactions but also and heparan sulfates. Cell surface anchorage contribute to self-assembly. The b- and g- sub- then enables the accumulation of nidogen, units primarily play a structural role, mediating type IV collagen, perlecan, and agrin to the nas- polymerization and nidogen-binding but also cent laminin scaffold. Although nonlaminin serve to modulate receptor-binding. Laminins- components have the potential to bind directly 111 and 511 (a5b1g1), the first to be expressed to cell surface integrins and/or dystroglycan, in mammalian embryos, are essential for base- they appear to be unable to accumulate on the ment membrane assembly and early embryonic cell surface to any appreciable degree in the ab- morphogenesis (Smyth et al. 1999; Huang et al. sence of laminins. Cell control of assembly, bio- 2003; Miner et al. 2004; Urbano et al. 2009). The logical activity, and subsequent state can occur laminin a1 subunit was found to be required for through the regulation of component expres- assembly of the extraembryonic Reichert’s sion, receptor expression, receptor activation, membrane whereas formation of the basement site-specific cleavage of laminin domains to membrane of the embryonic plate required alter their interactions, enzymatic cross-linking, either the Lma1orLma5 subunit (Miner and turnover/degradation

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