1. ¹Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, University of Washington Medicine at South Lake Union, Seattle, Washington, USA
2. ²Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington, USA
3. ³Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Correspondence: CK Abrass, Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, University of Washington Medicine at South Lake Union, 815 Mercer Street, Seattle, Washington 98109, USA. E-mail: cabrass@u.washington.edu

⁴Current address: Seagen, 21823 – 30th Drive S.E., Bothell, Washington 98021, USA

Received 25 January 2006; Revised 22 May 2006; Accepted 31 May 2006; Published online 19 July 2006.

Abstract

Mice with targeted disruption of the lama3 gene, which encodes the 3 chain of laminin-5 (332, 332), develop a blistering skin disease similar to junctional epidermolysis bullosa in humans. These animals also develop abnormalities in glomerulogenesis. In both wild-type and mutant animals (lama3^-/-), podocytes secrete glomerular basement membrane and develop foot processes. Endothelial cells migrate into this scaffolding and secrete a layer of basement membrane that fuses with the one formed by the podocyte. In lama3^-/- animals, glomerular maturation arrests at this stage. Endothelial cells do not attenuate, develop fenestrae, or form typical lumens, and mesangial cells (MCs) were not identified. LN 3 subunit (LAMA3) protein was identified in the basement membrane adjacent to glomerular endothelial cells (GEnCs) in normal rats and mice. In developing rat glomeruli, the LAMA3 subunit was first detectable in the early capillary loop stage, which corresponds to the stage at which maturation arrest was observed in the mutant mice. Lama3 mRNA and protein were identified in isolated rat and mouse glomeruli and cultured rat GEnCs, but not MC. These data document expression of LAMA3 in glomeruli and support a critical role for it in GEnC differentiation. Furthermore, LAMA3 chain expression and/or another product of endothelial cells are required for MC migration into the developing glomerulus.