Mini reviewsThe nature and biology of basement membranes
Introduction
Basement membranes (BMs) are cell-adherent extracellular matrices widely distributed in metazoan tissues. First identified in skeletal muscle 176 years ago [1], elucidation of BM constituents, structure, functions and genetics has required advances in multiple fields stretched over many years. The beginning of a molecular understanding of BMs dates to the 1970s and 1980s when Kefalides discovered collagen IV and Kuhn, Timpl, Martin, Bruckner, Robey, Rhode and others exploited the Engelbreth-Holm-Swarm tumor as a source for obtaining soluble BM components for analysis. Since then, a combination of biochemical, biophysical, cell biological, genetic, bioengineering and other approaches led to our current understanding of BMs. We are pleased to present a special edition of Matrix Biology entitled “Basement Membranes in Health and Disease” containing a collection of twenty-six articles from specialists in the field where the physiological and pathological functions of BM components are critically assessed.
Section snippets
How many proteins are incorporated into a typical basement membrane?
The core structural components of BMs are laminins, collagen IV, nidogens, and the heparan sulfate proteoglycans (HSPGs) perlecan and agrin (Fig. 1). We envision core components as those macromolecules for which there is an embryonic phenotype of failed or structurally-defective BM assembly upon knockout with the provision that compensation can sometimes mask a structure-forming role. These glycoproteins and proteoglycans, initially secreted in a soluble state, become organized into insoluble
Evolution and embryogenesis of basement membranes
Laminin domains integrated within proteins such as cadherins exist in single-cell motile choanoflagellates representing primitive species that pre-date the evolutionary emergence of BMs [4]. These unicellular organisms can aggregate to form clusters, suggesting BM/cadherin precursors serve cell-cell adhesive functions. BMs are thought to have first emerged in metazoans as a requirement for organizing epithelial tissues. Laminin α-like, β-like and γ-like subunits, each with a laminin N-terminal
Basement membrane assembly
Basement membrane formation is largely one of self-assembly involving cell surface adhesion, inter-component binding and polymerization. Laminins, by binding to cells, self, and other BM components, are essential for initiating this process. Laminin assembly is receptor-facilitated, occurs on “competent” cell surfaces that express laminin-binding molecules and is accompanied by polymerization mediated by the LN domains [12]. The BM, in good part through laminins, is anchored to integrin and
Mechano/chemical signaling mechanisms
Both mechanical and chemical interactions of BM and integrins and other receptors are required for cell signaling [15]. A breakthrough in our understanding of the mechanical role came from a study showing that matrix stiffness is capable of driving cell differentiation through different pathways [16]. This contribution has largely been explored with synthetic gels whose viscoelastic properties can be manipulated and that are attached to integrin ligands at known density. An emerging concept is
Human genetic diseases linked to basement membrane constituents: can we survive without basement membranes?
Defects of BM components such as the Lmγ1 chain, essential for embryogenesis, are presumed to result in embryonic death well before diseases might become manifest. Non-embryonic-lethal mutations in BM component genes are found for other laminin subunits, collagen IV, and perlecan. Several of these diseases are briefly discussed below and summarized in Table 1.
One set of laminin disorders are the Lmα2/merosin-deficient congenital muscular dystrophies (MDC1A and limb-girdle type) arising from
Can we answer some of the key questions in basement membrane biology?
So far we have dwelled on demonstrating how BMs are important for the maintenance of tissue homeostasis and how they function in various diseases processes. In this special issue a number of leading investigators of various aspects of BM biology will attempt to answer some biologically-relevant questions. Compositionally, BMs are tissue and organ specific, as clearly shown by proteomic analysis of BMs isolated from various tissues (Randles MJ et al.). The demonstration that BMs are important
Future research questions and directions
Although we are beginning to gain a systematic understanding of BM in biology, many challenges face us going forward. For example, we have a poor understanding of BM turnover, particularly during embryogenesis and following injury. We need to better understand the reason for having different isoforms of laminins, nidogens, and collagen IV during and after embryonic development. BM proteins all have multiple domains with functions assigned to a minority of loci. Are the other domains simply
Acknowledgments
The original research was supported in part by a Veteran's Affairs Merit Awards 1I01BX002025 (to AP), the National Institutes of Health Grants, R01DK095761 (to AP), R01/R37 DK36425 (to PDY), and by the National Institutes of Health grants RO1 CA39481, RO1 CA47282, and RO1 CA164462 (to RVI). AP is the recipient of a VA Senior Research Career Scientist.
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