Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction.
Both SRC-1 and TIF2 are members of the p160 steroid receptor coactivator family. Genetic analyses have shown that inactivation of TIF2, but not SRC-1, reduces postnatal survival, growth, and male reproductive function. Here, we demonstrate that, through analyses of SRC-1/TIF2 compound mutant mice, SRC-1 can partially compensate for the effects of a loss of TIF2 on mouse survival and growth, whereas SRC-1 and TIF2 are dispensable for primary organogenesis. The highly variable onset of defects observed in TIF2(-/-) testes due to the absence of TIF2 in Sertoli cells, including abnormal spermiogenesis, age-dependent degeneration of seminiferous epithelium, and disorder of cholesterol homeostasis, is uniformly accelerated upon inactivation of SRC-1 alleles in the TIF2 null genetic background, thus demonstrating that TIF2 and SRC-1 can perform redundant functions in Sertoli cells. Massive desquamation of immature germ cells together with an increase in germ cell apoptosis and a decrease in germ cell proliferation may be responsible for the early onset of the severe seminiferous epithelial degeneration observed in SRC-1(+/-)/TIF2(-/-) testes. Interestingly, the overall abnormal features displayed by the SRC-1(+/-)/TIF2(-/-) and SRC-1(-/-)/TIF2(-/-) mutant testes, including spermatid maturation defects, increase in Sertoli cell lipid stores, loss of immature germ cells, and formation of giant multinucleated spermatids, are commonly detected in testes of elderly men, suggesting that deficiencies in molecular pathways involving TIF2 and SRC-1 in Sertoli cells could participate in testicular senescence.
Mark
Manuel
M
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yoshida-Komiya
Hiromi
H
Gehin
Martine
M
Liao
Lan
L
Tsai
Ming-Jer
MJ
O'Malley
Bert W
BW
Chambon
Pierre
P
Xu
Jianming
J
D000375:Aging; D000818:Animals; D017209:Apoptosis; D003433:Crosses, Genetic; D003643:Death; D005260:Female; D006128:Growth / Q000502:physiology*; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D011650:Pulmonary Alveoli / Q000254:growth & development; D011987:Receptors, Steroid / Q000502:physiology*; D012708:Sertoli Cells / Q000473:pathology*; D013076:Sperm Count; D013091:Spermatogenesis; D013094:Spermatozoa / Q000473:pathology; D013737:Testis / Q000254:growth & development / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D011987:Receptors, Steroid; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1