Synergistic activities of alpha 3 and alpha 6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse

Integrins alpha 6 beta 1 and alpha 6 beta 4 are cell surface receptors for laminins. Integrin alpha 6-null mice die at birth with severe skin blisteri ng and defects in the cerebral cortex and in the retina. Integrin alpha 3 b eta 1 can associate with laminins and other ligands, Integrin alpha 3-null mice also die at birth, with kidney and lung defects at late stages of deve lopment, and moderate skin blistering. To investigate possible overlapping functions between alpha 3 and alpha 6 integrins, we analyzed the phenotype of compound alpha 3(-/-)/alpha 6(-/-) mutant embryos. Double homozygous mut ant embryos were growth-retarded and displayed several developmental defect s not observed in the single mutant animals. First, limb abnormalities char acterized by an absence of digit separation and the fusion of preskeletal e lements were observed. Further analyses indicated a defect in the apical ec todermal ridge, an essential limb organizing center. In the double mutant, the ridge appeared flattened, and ridge cells did not show a columnar morph ology. A strong reduction in ridge cell proliferation and alterations of th e basal lamina underlying the ectoderm were observed. These results suggest that alpha 3 and alpha 6 integrins are required for the organization or co mpaction of presumptive apical ectodermal ridge cells into a distinct diffe rentiated structure. Additional defects were present: an absence of neural tube closure, bilateral lung hypoplasia, and several abnormalities in the u rogenital tract, Finally, an aggravation of brain and eye lamination defect s was observed. The presence of novel phenotypes in double mutant embryos d emonstrates the synergism between alpha 3 and alpha 6 integrins and their e ssential roles in multiple processes during embryogenesis.