Targeted Disruption of the LAMA3 Gene in Mice Reveals Abnormalities in Survival and Late Stage Differentiation of Epithelial Cells

doi:10.1083/jcb.145.6.1309

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© The Rockefeller University Press, 0021-9525/1999//1309 $5.00
The Journal of Cell Biology, Volume 145, Number 6, , 1999 1309-1324

Article

Targeted Disruption of the LAMA3 Gene in Mice Reveals Abnormalities in Survival and Late Stage Differentiation of Epithelial Cells

Maureen C. Ryan^*^,, Keesook Lee, Yuko Miyashita^*, and William G. Carter^*^,||

^* Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington 98198; ^|| Department of Pathobiology, University of Washington, Seattle, Washington 98198; and Hormone Research Center, Chonnam National University, Kwangju 500-757, South Korea

Laminin 5 regulates anchorage and motility of epithelial cellsthrough integrins ${alpha}$ 6β4 and ${alpha}$ 3β1, respectively. We usedtargeted disruption of the LAMA3 gene, which encodes the ${alpha}$ 3subunit of laminin 5 and other isoforms, to examine developmentalfunctions that are regulated by adhesion to the basement membrane(BM). In homozygous null animals, profound epithelial abnormalitieswere detected that resulted in neonatal lethality, consistentwith removal of all ${alpha}$ 3-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 ${alpha}$ 6β4,consistent with the presence of junctional blisters and abnormalhemidesmosomes. In the absence of laminin 5 function, we wereable to detect a new ligand for integrin ${alpha}$ 3β1 in the epidermalBM, suggesting that basal keratinocytes can utilize integrin ${alpha}$ 3β1 to interact with an alternative ligand. Second, weidentified a survival defect in mutant epithelial cells that could be rescued by exogenous laminin 5, collagen, or an antibodyagainst integrin ${alpha}$ 6β4, suggesting that signaling throughβ1 or β4 integrins is sufficient for survival. Third,we detected abnormalities in ameloblast differentiation indeveloping mutant incisors indicating that events downstreamof adhesion are affected in mutant animals. These results indicatethat laminin 5 has an important role in regulating tissue organization, gene expression, and survival of epithelium.

Key Words: laminin 5 • integrins • cell adhesion • epithelial cells • junctional epidermolysis bullosa

Abbreviations used in this paper: BM, basement membrane; BMZ, basement membrane zone; BP180, bullous pemphigoid antigen 180; BP230, bullous pemphigoid antigen 230; ECM, extracellular matrix; ES, embryonic stem; HD, hemidesmosome; HFK, human foreskin keratinocyte; JEB-G, junctional epidermolysis bullosa gravis; KGM, keratinocyte growth medium; MEK, mouse epidermal keratinocyte.

The authors would like to acknowledge financial support fromthe National Institutes of Health Grants CA49259 and AR-21557to W.G. Carter and the Dermatology Foundation (M.C. Ryan).

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