Developmental and pathogenic mechanisms of basement membrane assembly

Abstract

Basement membranes are sheet-like cell-adherent extracellular matrices that serve as cell substrata and solid-phase agonists, contributing to tissue organization, stability and differentiation. These matrices are assembled as polymers of laminins and type IV collagens that are tethered to nidogens and proteoglycans. They bind to cell surface molecules that include signal-transducing receptors such as the integrins and dystroglycan and form attachments to adjacent connective tissues. The cell receptors, in turn, provide links between the matrix and underlying cytoskeleton. Genetic diseases of basement membrane and associated components, collectively the basement membrane zone, disrupt the extracellular matrix and/or its linkages to affect nerve, muscle, skin, kidney and other tissues. These diseases can arise due to a loss of matrix integrity, adhesion strength and/or receptor-mediated signaling. An understanding of the mechanisms of basement membrane zone assembly and resulting structure can provide insights into the development of normal tissues and the pathogenic mechanisms that underlie diverse disorders.

Fig. (1). Basement Membrane Components and Interactions

Examples are shown for major laminins. Each possesses three subunits and possesses globular, rod-like and coiled-coil domains (these are indicated for laminin-111). Various proteolytic cleavages (jagged lines) generate additional diversity. Each type IV collagen is a heterotrimer with three different chain compositions (most common is α1₂α2[IV]). In addition are found two nidogens (Nd1, Nd2), and the heparan sulfate proteoglycans agrin (Ag) and perlecan (perl). Major binding and minor (heavy and thin dashed arrows) binding interactions are indicated among the structural components (black lines) and with cell surface components (green lines to integrins, α-dystroglycan (αDG), hemidesmosomal (HD) BP180, sulfated glycolipids (SGL) and the Lutheran (Lu) antigen. In squamous epithelia, laminin 3A32 is processed by several proteases. It binds to the α6β4 integrin and BP180 and binds to type VII collagen.

Fig. (2). Basement Membrane Assembly

In this simplified model, laminins become anchored to the cell surface through their LG domains. Anchorage is further enhanced through binding of the α-LN domain to sulfated glycolipids. If the laminin has three LN domains it polymerizes, creating a “nascent” scaffolding. Nidogens, type IV collagens, perlecan, and agrin, are incorporated into this initial matrix by binding to laminin (or by binding through a nidogen bridge). The type IV collagen self-assembles into a covalently-crosslinked network. The non-laminin components provide crucial stability and increase ligand complexity. The basement membrane ligands interact with integrins and dystroglycan and the heparan sulfates of agrin and perlecan enable the tethering of tissue-specific growth factors.

Fig. (3). Cytoskeletal Linkages

Basement membrane ligands can establish links to the actin and keratin cytoskeletons by binding to integrins and dystroglycan. (a) β1-integrins: Nearly all basement membrane components bind to β1-integrins. These integrins bind to cytoskeletal intermediates that bind to F-actin. The intermediates shown are integrin linked kinase (ILK) and α- and β-parvin, α-actinin (act), talin (tal) vinculin (Vn) and Arp2/3, and filamin (fil) (drawing after [45]). (b) Dystroglycan: The LG domains of laminins, agrin and perlecan bind to α-dystroglycan (αDG). αDG binds to β-dystroglycan, a transmembrane protein that binds to F-actin through dystrophin and utrophin. In muscle, dystroglycan is part of a complex that includes the sarcoglycans and other proteins. Homologues of dystrophin and utrophin exist in other tissues. (c) α6β4-integrin: Laminin 332 binds to this unique integrin that forms part of hemidesmosome complexes and that forms a linkage with keratin filaments [14].