Skin basement membrane: the foundation of epidermal integrity--BM functions and diverse roles of bridging molecules nidogen and perlecan

Abstract

The epidermis functions in skin as first defense line or barrier against environmental impacts, resting on extracellular matrix (ECM) of the dermis underneath. Both compartments are connected by the basement membrane (BM), composed of a set of distinct glycoproteins and proteoglycans. Herein we are reviewing molecular aspects of BM structure, composition, and function regarding not only (i) the dermoepidermal interface but also (ii) the resident microvasculature, primarily focusing on the per se nonscaffold forming components perlecan and nidogen-1 and nidogen-2. Depletion or functional deficiencies of any BM component are lethal at some stage of development or around birth, though BM defects vary between organs and tissues. Lethality problems were overcome by developmental stage- and skin-specific gene targeting or by cell grafting and organotypic (3D) cocultures of normal or defective cells, which allows recapitulating BM formation de novo. Thus, evidence is accumulating that BM assembly and turnover rely on mechanical properties and composition of the adjacent ECM and the dynamics of molecular assembly, including further "minor" local components, nidogens largely functioning as catalysts or molecular adaptors and perlecan as bridging stabilizer. Collectively, orchestration of BM assembly, remodeling, and the role of individual players herein are determined by the developmental, tissue-specific, or functional context.

Figure 1

Schematic view of the basement membrane (BM). (a) The general molecular array leading to the mat-like BM texture and (b) the interactions between the four major individual BM components based on in vitro binding data.

Figure 2

Ultrastructural elements (a–d) of the basement membrane (BM) zone in skin, ultrastructural alignments (b–d), and prototypes of laminin isoforms (e). The cartoon (a) depicts the anchoring structures between epidermis (E) and dermis (D) corresponding to the ultrastructure of the collagen-epidermal interface (b) of a 3D coculture of keratinocytes with fibroblasts, resembling skin. Immune-EM demonstrates the coalignment of collagen IV with the lamina densa (c) and colocalization of integrin α6β4 with laminin-332 ((d); small/large gold particles). Three laminin subtypes, being also present in adult skin, are shown in (e), represented by the main adult BM-type laminin-511, the vascular laminin-411, and laminin-332 found in anchoring filaments. Like laminin-511, most isoforms carry three N-terminal self-assembly sites (∗) required for two-dimensional polymerization. Some other like laminin-411 have only two, and, as an exception, laminin-332 has only one of those “sticky” sites. Common to all are the C-terminal cell-binding sites (∗∗); large arrows point to the γ1 nidogen-binding domain. Further typical for laminin-332 is extensive proteolytic processing with the major cleavage sites (marked by small arrows) at the short arm of the γ2 and the C-terminus of the α3 chain (see also: [78, 125]). (Slightly modified from [18] [with kind permission from Springer Science + Business Media]).