Basement Membranes in Development and Disease

Abstract

The basement membrane is a thin but dense, sheet-like specialized type of extracellular matrix that has remarkably diverse functions tailored to individual tissues and organs. Tightly controlled spatial and temporal changes in its composition and structure contribute to the diversity of basement membrane functions. These different basement membranes undergo dynamic transformations throughout animal life, most notably during development. Numerous developmental mechanisms are regulated or mediated by basement membranes, often by a combination of molecular and mechanical processes. A particularly important process involves cell transmigration through a basement membrane because of its link to cell invasion in disease. While developmental and disease processes share some similarities, what clearly distinguishes the two is dysregulation of cells and extracellular matrices in disease. With its relevance to many developmental and disease processes, the basement membrane is a vitally important area of research that may provide novel insights into biological mechanisms and development of innovative therapeutic approaches. Here we present a review of developmental and disease dynamics of basement membranes in Caenorhabditis elegans, Drosophila, and vertebrates.

Keywords: Basement membrane; Basement membrane pores; Cancer; Cell migration; Development; Extracellular matrix; Invasion; Morphogenesis; Proliferation.

Figure 1.. Schematics of basement membranes (BMs) in various tissues.

(A) Blood-brain barrier: endothelial and parenchymal BMs surround the brain capillary. (B) Eye: retinal pigment epithelium BM, choroid BM, and an intermediate collagenous zone comprise the Bruch’s membrane. (C) Lung: endothelial and alveolar BMs merge to provide a site for gas exchange. (D) Tissues surrounding teeth: junctional epithelium adheres to the enamel via the internal basal lamina and to the mesenchyme via the external basal lamina. The oral gingival epithelium BM is adjacent to the oral epithelium. (E) Skin: cutaneous BM underlies basal epithelial cells. (F) Kidney: during development, endothelial and podocyte-derived epithelial BMs merge to form the glomerular BM. Figures are not drawn to scale.

Figure 2.. Basic structure of the BM.

(A) Collagen IV network. (B) Laminin network. (C) Schematic representation of the BM with its major components.

Figure 3.. The BM of embryonic mouse tooth bud.

(A) The basement membrane underlies the oral epithelium and surrounds inner and outer enamel epithelia of the enamel organ. The dental papilla lies beneath the inner enamel epithelium and gives rise to the dentin and pulp. (B) Laminin γ1 and nidogen-2 are expressed around the tooth bud. (C) FRAS1 and FREM1 show a spatially specific expression pattern along the inner enamel epithelium. (D) A gradient expression pattern of netrin-1 is found subjacent to the primary enamel knot.

Figure 4.. Basic structure of dental supporting basal laminae.

(A) Schematic illustration of basal laminae around a tooth. (B) Desmosomes mediate intercellular adhesions. Hemidesmosomes mediate attachment of internal and external basal laminae to enamel and mesenchyme, respectively.

Figure 5.. BM micro-perforations in embryonic mouse submandibular salivary gland.

Micro-perforations are prominent at the tip of epithelial buds. These perforations gradually disappear towards the equator (dotted line). As the growing buds expand rapidly, the number of perforations peaks at embryonic day (E) 13.5. Basement membrane translocation away from the bud tip is accompanied by accumulation of fibril-like basement membrane proteins at the forming secondary duct.

Figure 6.. Factors involved in C. elegans BM transmigration.

The first stage is initiated by cell cycle arrest and activation of a transcriptional cascade that lead to invadopodia formation. The second stage involves netrin-DCC signaling that directs growth of a single large cellular protrusion, allowing the anchor cell to breach the juxtaposed uterine and vulval basement membranes.