Integrin α8β1 Is Critically Important for Epithelial–Mesenchymal Interactions during Kidney Morphogenesis

Pichel et al., 1996; Sanchez et al., 1996; Schuchardt et We present genetic evidence that integrins regulate al., 1996). A number of transcription factors, including epithelial–mesenchymal interactions during organoWT-1, Pax-2, and BF-2, are also required for kidney genesis. Mice with a mutation in the a8 gene do not development (Kreidberg et al., 1993; Torres et al., 1995; express the integrin a8b1 and exhibit profound deficits Hatini et al., 1996). Transcription factors and signaling in kidney morphogenesis. In wild-type animals, inducmolecules must regulate expression levels and activities tive interactions between the ureteric epithelium and of downstream targets that execute the imposed develmetanephric mesenchyme are essential for kidney opmental program. Among strong candidates for downmorphogenesis. In a8 mutant homozygotes, growth stream targets are integrins, a family of heterodimeric and branching of the ureteric bud and recruitment of cell surface proteins that serve as receptors for extracelmesenchymal cells into epithelial structures are delular matrix (ECM) molecules and counterreceptors on fective. Consistent with these phenotypes, a8 expresadjacent cells (reviewed in Hynes, 1992). Experiments sion is induced in mesenchymal cells upon contact with kidney organ cultures have provided evidence that with the ureter. Since none of its previously identified integrin receptors and their ligands regulate the develligands appears likely to mediate the essential funcopment of polarized epithelia from metanephric mesentions of a8b1 in kidney morphogenesis, we have used chymal cells following induction by the ureteric epithean a8b1–alkaline phosphatase chimera to localize lium (reviewed in Ekblom, 1996). novel ligand(s) in the growing ureter. The distribution We now demonstrate that integrins are required in of these ligand(s) makes them strong candidates for vivo for kidney morphogenesis. We have previously regulators of kidney morphogenesis. shown that the integrin a8 subunit forms heterodimers