Overlapping and independent functions of fibronectin receptor integrins inearly mesodermal development

Mouse embryos deficient in fibronectin (FN-null) die at E8.5 with mesoderma l defects. Eight integrin heterodimers alpha 3 beta 1, alpha 4 beta 1, alph a 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, raisi ng questions as to which integrin(s) are the key FN receptors for these ear ly EN-dependent processes. alpha 5 beta 1 is believed to be the key recepto r 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 mu tation 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 embryo s 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-nu ll embryos, however, cannot be attributed to genetic background. FN-null em bryos never form somites, whereas in (alpha 5-null/129 embryos the somites do condense but fail to epithelialize. Second, we examined double mutants c arrying all possible pairwise combinations of null mutations in alpha 3, al pha 4, and alpha 5 integrin genes. There was no evidence for any synergy be tween paired mutations, suggesting that these integrin genes do not have ov erlapping functions during early embryonic development. Finally, we examine d double-mutant embryos deficient in both alpha 5 and alpha v integrin gene s. These double-mutant embryos have an amniotic defect similar to that of E N-null embryos, but die even earlier with a defect in gastrulation. These s tudies thus revealed a gradation in the severity of defects in the mutation s alpha 5(-/-) ; alpha v(-/-) > FN-/- (129) > FN-/- (B6) > alpha 5(-/-) (12 9) > alpha 5(-/-) (B6), and in each step in this series there is a certain degree of phenotypic overlap, suggesting that the defects arising from thes e mutations may result from disruptions of the same embryonic process. (C) 1999 Academic Press.