Seminiferous tubule degeneration and infertility in mice with sustained activation of WNT/CTNNB1 signaling in sertoli cells.
WNT/CTNNB1 signaling is involved in the regulation of multiple embryonic developmental processes, adult tissue homeostasis, abd cell fate determination and differentiation. Many WNTs and components of the WNT/CTNNB1 signaling pathway are expressed in the testis, but their physiological roles in this organ are largely unknown. To elucidate the role(s) of WNT/CTNNB1 signaling in the testis, transgenic Ctnnb1 tm1Mmt/+;Amhr2 tm3(cre)Bhr/+ mice were generated to obtain sustained activation of the WNT/CTNNB1 pathway in both Leydig and Sertoli cells. Male Ctnnb1 tm1Mmt/+;Amhr2 tm3(cre)Bhr/+ mice were sterile because of testicular atrophy starting at 5 wk of age, associated with degeneration of seminiferous tubules and the progressive loss of germ cells. Although Cre activity was expected in Ctnnb1 tm1Mmt/+;Amhr2 tm3(cre)Bhr/+ Leydig cells, no evidence of Cre-mediated recombination of the floxed allele or of WNT/CTNNB1 pathway activation could be obtained, and testosterone levels were comparable to age-matched controls, suggesting that genetic recombination was inefficient in Leydig cells. Conversely, sustained WNT/CTNNB1 pathway activation was obtained in Ctnnb1 tm1Mmt/+;Amhr2 tm3(cre)Bhr/+ Sertoli cells. The latter often exhibited morphological characteristics suggestive of incomplete differentiation that appeared in a manner coincident with germ cell loss, and this was accompanied by an increase in the expression of the immature Sertoli cell marker AMH. In addition, a poorly differentiated, WT1-positive somatic cell population accumulated in multilayered foci near the basement membrane of many seminiferous tubules. Together, these data suggest that the WNT/CTNNB1 pathway regulates Sertoli cell functions critical to their capacity to support spermatogenesis in the postnatal testis.
Boyer
Alexandre
A
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Hermo
Louis
L
Paquet
Marilène
M
Robaire
Bernard
B
Boerboom
Derek
D
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012671:Seminiferous Tubules / Q000378:metabolism / Q000473:pathology*; D012708:Sertoli Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013091:Spermatogenesis / Q000235:genetics; D013733:Testicular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
C495267:CTNNB1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases