Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
The Rho small G protein family members regulate various actin cytoskeleton-dependent cell functions. The Rho GDI (GDP dissociation inhibitor) family, consisting of Rho GDIalpha, -beta, and -gamma, 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 GDIalpha is ubiquitously expressed in mouse tissues and shows GDI activity on all the Rho family members in vitro. We have generated mice lacking Rho GDIalpha by homologous recombination to clarify its in vivo function. Rho GDIalpha -/- mice showed several abnormal phenotypes. Firstly, Rho GDIalpha -/- 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 GDIalpha -/- male mice were infertile and showed impaired spermatogenesis with vacuolar degeneration of seminiferous tubules in their testes. Thirdly, Rho GDIalpha -/- embryos derived from Rho GDIalpha -/- 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 GDIalpha play important roles in maintaining the structure and physiological function of at least kidneys and reproductive systems in adult mice.
Togawa
A
A
Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co., Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.
Miyoshi
J
J
Ishizaki
H
H
Tanaka
M
M
Takakura
A
A
Nishioka
H
H
Yoshida
H
H
Doi
T
T
Mizoguchi
A
A
Matsuura
N
N
Niho
Y
Y
Nishimune
Y
Y
Nishikawa
S i
Si
Takai
Y
Y
D000367:Age Factors; D000818:Animals; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007248:Infertility, Male / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009404:Nephrotic Syndrome / Q000209:etiology / Q000235:genetics; D051437:Renal Insufficiency / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000473:pathology; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C569639:Arhgdia protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors