Trends in Genetics
Volume 16, Issue 9, 1 September 2000, Pages 389-395
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Integrin and ECM functions: roles in vertebrate development

https://doi.org/10.1016/S0168-9525(00)02074-6Get rights and content

Abstract

The analysis of mutant mice is bringing novel insights on the role of extracellular matrix (ECM) and integrin receptors during a variety of physiological processes, including embryonic development. The requirement of these adhesion molecules in epithelial morphogenesis or histogenesis in organs such as kidneys and lungs, in limbs, and in the development of mesoderm and the nervous system has been unraveled by the study of single or compound mutants. Their role in tissue integrity has also been highlighted. Models have been produced that should prove very useful in defining the cellular mechanisms and the functions of integrins and ECM signaling cascades in vivo.

Section snippets

Basement membranes in development

The essential role of the ECM during embryogenesis was first illustrated by the knockout of the gene for fibronectin (FN)9, 10. More recent data now concerns components of the basement membranes (BMs), the highly specialized sheet-like structures that surround or separate tissue compartments. Basement membranes contain laminins, collagen IV, nidogen/entactin and proteoglycans. Laminins (LNs) are αβγ heterotrimeric glycoproteins that represent the major noncollagenous BM components. This

Integrins

Integrins are heterodimeric transmembrane receptors composed of noncovalently associated α and β chains (Fig. 1). More than 20 integrin heterodimers have been identified, which recognize ECM components (laminins, collagens, fibronectins and others) as well as counter-receptors on the surface of neighboring cells2. Many integrins can bind several ligands, and generally, one ligand is recognized by several integrin heterodimers. As has become obvious during recent years in studies of cultured

Overlap or synergism between integrins

Mild or late phenotypes in integrin-deficient embryos suggest that there might be some overlapping functions between several integrins. This could be expected because, in general, one ECM ligand can bind to several receptors, and one integrin can bind several ligands. Two very recent studies have illustrated this point.

A result that remained puzzling for a few years was the observation that the targeted inactivation of integrins corresponding to FN receptors yielded phenotypes less severe than

Ligand–receptor relationships in vivo

Genetics have also been very useful to define the integrin– ligand relationship. In several cases, by comparing the phenotypes of mice deficient for ECM ligands and integrin receptors, it has been very clearly demonstrated which receptor and ligand are essential in vivo.

Intracellular functions of integrins

As mentioned above, defects in cell proliferation or survival, or both, have been observed in knockout animals, which support the hypothesis coming from cellular studies that integrins are part of the signaling machinery that controls cell behavior.

How do the knockouts help us to understand integrin signaling? Examination of mutant cells has been informative in the case of the integrin α1 chain mutation (Table 2). Integrin α1β1 is a major receptor for collagens. Integrin α1 null mice are viable

Future studies

The genetic approach has already allowed the precise allocation of functions to the ECM and integrin molecules in specific morphogenetic processes (Box 1), and will most probably be even more informative in the near future with the use of strategies for conditional tissue- and stage- specific knockouts. Interestingly, several systems in which these adhesion molecules have been shown to play a role (limbs, lungs and kidneys) are systems in which morphogenetic signals (such as fibroblast growth

Acknowledgements

A.D. is a recipient of a fellowship from the Association pour la Recherche sur le Cancer (ARC). Our research is supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Hôpital Universitaire de Strasbourg (HUS), and grants from ARC, and the CNRS program ‘Biologie Cellulaire’.

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