Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect.
GATA3 is a zinc finger transcription factor that plays a crucial role in embryonic kidney development, while its precise functions in the adult kidney remain largely unexplored. Here, we demonstrate that GATA3 is specifically expressed in glomerular mesangial cells and plays a critical role in the maintenance of renal glomerular function. Newly generated Gata3 hypomorphic mutant mice exhibited neonatal lethality associated with severe renal hypoplasia. Normal kidney size was restored by breeding the hypomorphic mutant with a rescuing transgenic mouse line bearing a 662-kb Gata3 yeast artificial chromosome (YAC), and these animals (termed G3YR mice) survived to adulthood. However, most of the G3YR mice showed degenerative changes in glomerular mesangial cells, which deteriorated progressively during postnatal development. Consequently, the G3YR adult mice suffered severe renal failure. We found that the 662-kb Gata3 YAC transgene recapitulated Gata3 expression in the renal tubules but failed to direct sufficient GATA3 activity to mesangial cells. Renal glomeruli of the G3YR mice had significantly reduced amounts of platelet-derived growth factor receptor (PDGFR), which is known to participate in the development and maintenance of glomerular mesangial cells. These results demonstrate a critical role for GATA3 in the maintenance of mesangial cells and its absolute requirement for prevention of glomerular disease.
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan moriguch@med.tohoku.ac.jp engel@umich.edu.
Takashi
T
Moriguchi
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Lei
L
Yu
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Akihito
A
Otsuki
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Keiko
K
Ainoya
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Kim-Chew
KC
Lim
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Masayuki
M
Yamamoto
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA moriguch@med.tohoku.ac.jp engel@umich.edu.
James Douglas
JD
Engel
D000818:Animals; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics*; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D019076:Transgenes
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D010982:Platelet-Derived Growth Factor