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Seminiferous Tubule Degeneration and Infertility in Mice with Sustained Activation of WNT/CTNNB1 Signaling in Sertoli Cells¹

Centre de Recherche en Reproduction Animale,³ Université de Montréal, St-Hyacinthe, Québec, Canada J2S 7C6 Department of Molecular and Cellular Biology,⁴ Baylor College of Medicine, Houston, Texas 77030 Department of Anatomy and Cell Biology,⁵ Comparative Medicine & Animal Resources Centre,⁶ and Department of Pharmacology and Therapeutics,⁷ McGill University, Montreal, Québec, Canada H3G 1Y6

ABSTRACT

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.

beta-catenin, Cre-lox, CTNNB1, Sertoli, Sertoli cells, spermatogenesis, testicular degeneration, WNT

¹ Supported by a Discovery Grant from the National Sciences and Engineering Research Council (NSERC) (to D.B.), the Canada Research Chair in Ovarian Molecular Biology and Functional Genomics (to D.B.), the Canadian Institutes of Health Research (to L.H., B.R.), a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec (FRSQ) (to A.B.), and NICHD (SCCPRR) grant U54-HD28934, "University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core."

Correspondence: ²Derek Boerboom, Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe (Québec), Canada J2S 7C6. FAX: 450 778 8103; e-mail: derek.boerboom{at}umontreal.ca