Trends in Genetics
ReviewsIntegrin and ECM functions: roles in vertebrate development
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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