Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα

Abstract

The Rho small G protein family members regulate various actin cytoskeleton-dependent cell functions. The Rho GDI (GDP dissociation inhibitor) family, consisting of Rho GDIa, -b, and -g, is a regulator that keeps the Rho family members in the cytosol as the GDP-bound inactive form and translocates the GDP-bound form from the membranes to the cytosol after the GTP-bound form accomplishes their functions. Rho GDIa is ubiquitously expressed in mouse tissues and shows GDI activity on all the Rho family members in vitro. We have generated mice lacking Rho GDIa by homologous recombination to clarify its in vivo function. Rho GDIa 7/7 mice showed several abnormal phenotypes. Firstly, Rho GDIa 7/7 mice were initially viable but developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year. Histologically, degeneration of tubular epithelial cells and dilatation of distal and collecting tubules were readily detected in the kidneys. Secondly, Rho GDIa 7/7 male mice were infertile and showed impaired spermatogenesis with vacuolar degeneration of seminiferous tubules in their testes. Thirdly, Rho GDIa 7/7 embryos derived from Rho GDIa 7/7 female mice were defective in the postimplantation development. In addition, these morphological and functional abnormalities showed age-dependent progression. These results suggest that the signaling pathways of the Rho family members regulated by Rho GDIa play important roles in maintaining the structure and physiological function of at least kidneys and reproductive systems in adult mice.

Nephrocystin interacts with Pyk2, p130 Cas , and tensin and triggers phosphorylation of Pyk2

“…Mice lacking ␣ 3 ␤ 1 , an integrin predominantly expressed in the podocyte, develop severe glomerular abnormalities but also display cystic changes of the proximal tubules (10). Finally, mice lacking GDI␣, a GDP dissociation inhibitor of the small GTPase Rho, develop marked proteinuria as well as a degeneration of tubular epithelial cells (11). These findings indicate that abnormalities of the cell matrix adhesion complex may result in the development of tubular basement abnormalities in combination with renal cysts.…”

Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

“…RhoGDIaK/K males have spermatogenesis defects and are infertile and RhoGDIaK/K females have implantation defects (Togawa et al 1999). Thus, RhoGDIa not only influences estrogen-responsive gene expression in MCF-7 breast cancer cells, but also has profound effects on the reproductive tract and reproduction.…”

Inherited Podocytopathies

“…Mice deficient in RhoGDI␣, a regulator of the Rho GDP dissociation inhibitor family, develop massive nephrosis (78). The importance of the Rho pathway in mediating cytoskeletal rearrangements again points to a disregulated cytokeleton as the cause of this phenotype.…”