Laminin 5 regulates anchorage and motility of epithelial cells through
integrins alpha6beta4 and alpha3beta1, respectively. We used targeted disruption of the LAMA3 gene, which encodes the alpha3 subunit of
laminin 5 and other
isoforms, to examine developmental functions that are regulated by adhesion to the basement membrane (BM). In homozygous null animals, profound epithelial abnormalities were detected that resulted in neonatal lethality, consistent with removal of all alpha3-laminin
isoforms from epithelial BMs. Alterations in three different cellular functions were identified. First, using a novel
tissue adhesion assay, we found that the mutant BM could not induce stable adhesion by
integrin alpha6beta4, consistent with the presence of junctional
blisters and abnormal hemidesmosomes. In the absence of
laminin 5 function, we were able to detect a new
ligand for
integrin alpha3beta1 in the epidermal BM, suggesting that basal keratinocytes can utilize
integrin alpha3beta1 to interact with an alternative
ligand. Second, we identified a survival defect in mutant epithelial cells that could be rescued by exogenous
laminin 5,
collagen, or an antibody against
integrin alpha6beta4, suggesting that signaling through beta1 or beta4
integrins is sufficient for survival. Third, we detected abnormalities in ameloblast differentiation in developing mutant incisors indicating that events downstream of adhesion are affected in mutant animals. These results indicate that
laminin 5 has an important role in regulating tissue organization, gene expression, and survival of epithelium.