Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene.
Mice with targeted disruption of the lama3 gene, which encodes the alpha3 chain of laminin-5 (alpha3beta3gamma2, 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 alpha3 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.
Abrass
C K
CK
Department 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. cabrass@u.washington.edu
Berfield
A K
AK
Ryan
M C
MC
Carter
W G
WG
Hansen
K M
KM
D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D001755:Blastocyst / Q000166:cytology; D002196:Capillaries / Q000378:metabolism / Q000648:ultrastructure; D002454:Cell Differentiation; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D018274:Electroporation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000098:blood supply / Q000648:ultrastructure; D007150:Immunohistochemistry; D007797:Laminin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050527:Mesangial Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011995:Recombination, Genetic; D013234:Stem Cells / Q000166:cytology
D024141:Collagen Type IV; D007797:Laminin; D012333:RNA, Messenger; C095567:laminin alpha 3