Submitted February 25, 2008
Returned for revision March 29, 2008
Accepted May 1, 2008
Testis
Seminiferous Tubule Degeneration and Infertility in Mice with Sustained Activation of WNT/CTNNB1 Signaling in Sertoli Cells
Alexandre Boyer ,
Louis Hermo ,
Marilène Paquet ,
Bernard Robaire ,
and
Derek Boerboom *
* To whom correspondence should be addressed. E-mail: derek.boerboom{at}umontreal.ca.
Abstract
WNT/CTNNB1 signaling is involved in the regulation of multiple embryonic developmental processes, adult tissue homeostasis, as well as in 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 Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ mice were generated to obtain sustained activation of the WNT/CTNNB1 pathway in both Leydig and Sertoli cells. Male Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ mice were sterile due to testicular atrophy starting at 5 weeks of age, associated with degeneration of seminiferous tubules and the progressive loss of germ cells. Although Cre activity was expected in Ctnnb1tm1Mmt/+;Amhr2tm3(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 Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ Sertoli cells. The latter often exhibited morphological characteristics suggestive of incomplete differentiation that appeared in a manner co-incident 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.
Key words:
Sertoli cells •
Spermatogenesis •
Cre-lox •
beta-catenin •
testicular degeneration
