Overlapping and independent functions of fibronectin receptor integrins in early mesodermal development

Mouse embryos deficient in fibronectin (FN-null) die at E8.5 with mesodermal defects. Eight integrin heterodimers alpha 3 beta 1, alpha 4 beta 1, alpha 5 beta 1, alpha 8 beta 1, alpha v beta 1, alpha v beta 3, alpha v beta 6, and alpha IIb beta 3 can bind to FN. However, embryos deficient in each of these integrins exhibit less severe defects than do EN-null embryos, raising questions as to which integrin(s) are the key FN receptors for these early EN-dependent processes. alpha 5 beta 1 is believed to be the key receptor and alpha 5-null embryos display mesodermal defects similar to, although less severe than, those of FN-null. Here we report that the alpha 5-null mutation exhibits a more severe phenotype on a 129Sv (129) than on a C57BL/6 (B6) background, as does the FN-null mutation. While alpha 5-null/B6 embryos develop normal headfolds, alpha 5-null/129 embryos have headfold defects similar to those of FN-null. The differences between EN-null and alpha 5-null embryos, however, cannot be attributed to genetic background. FN-null embryos never form somites, whereas in (alpha 5-null/129 embryos the somites do condense but fail to epithelialize. Second, we examined double mutants carrying all possible pairwise combinations of null mutations in alpha 3, alpha 4, and alpha 5 integrin genes. There was no evidence for any synergy between paired mutations, suggesting that these integrin genes do not have overlapping functions during early embryonic development. Finally, we examined double-mutant embryos deficient in both alpha 5 and alpha v integrin genes. These double-mutant embryos have an amniotic defect similar to that of EN-null embryos, but die even earlier with a defect in gastrulation. These studies thus revealed a gradation in the severity of defects in the mutations alpha 5(-/-) ; alpha v(-/-) > FN-/- (129) > FN-/- (B6) > alpha 5(-/-) (129) > alpha 5(-/-) (B6), and in each step in this series there is a certain degree of phenotypic overlap, suggesting that the defects arising from these mutations may result from disruptions of the same embryonic process. (C) 1999 Academic Press.