Defective Glomerulogenesis in the Absence of Laminin α5 Demonstrates a Developmental Role for the Kidney Glomerular Basement Membrane

Abstract

Laminins are major components of all basement membranes. They are a diverse group of α/β/γ heterotrimers formed from five α, three β, and three γ chains. Laminin α5 is a widely expressed chain found in many embryonic and adult basement membranes. During embryogenesis, α5 has a role in disparate developmental processes, including neural tube closure, digit septation, and placentation. Here, we analyzed kidney development in Lama5 mutant embryos and found a striking defect in glomerulogenesis associated with an abnormal glomerular basement membrane (GBM). This correlates with failure of the developmental switch in laminin α chain deposition in which α5 replaces α1 in the GBM at the capillary loop stage of glomerulogenesis. In the absence of a normal GBM, glomerular epithelial cells were in disarray, and endothelial and mesangial cells were extruded from within the constricting glomerulus, leading to a complete absence of vascularized glomeruli. In addition, a minority of Lama5 mutant mice lacked one or both kidneys, indicating that laminin α5 is also important in earlier kidney development. Our results demonstrate a dual role for laminin α5 in kidney development, illustrate a novel defect in glomerulogenesis, and indicate a heretofore unappreciated developmental role for the GBM in influencing the behavior of epithelial and endothelial cells.