Juvenile spermatogonial depletion (jsd) mice initiate a wave of spermatogenesis at puberty, but then sperm differentiation ceases despite the continued presence of A spermatogonia. Although the mechanism is not known, we showed that testosterone (T) inhibits spermatogonial differentiation, which can be restored with GnRH antagonist or estradiol (E2). We hypothesize that inhibition of spermatogonial differentiation in jsd mice is due to the action of T on gene expression in a specific somatic cell (Sertoli, Leydig, peritubular myoid, or arteriolar smooth muscle). We utilize the power of mouse genetics to elucidate the mechanism by which T mediates spermatogonial """"""""arrest"""""""" in jsd mice and begin identifying the cell type and hormonally regulated gene(s) involved in the following Aims: (I) To establish the specific role of androgen and not FSH, we will complete studies using jsd mice also carrying mutations in the androgen receptor (AR) and FSHbeta genes. To determine the mode and the site of action of E2, the restoration of spermatogenesis with GnRH-antagonist and E2 treatment will be compared in jsd mice with that in jsd mice carrying mutations for estrogen receptor (ER)-alpha or for ERbeta. (II) To establish that the hormones affect spermatogonial differentiation by direct action on the testis and/or seminiferous tubules, we will examine their effects on spermatogonia in in vitro cultures of testicular tissue and tubules from jsd mice. (III) To identify the cell that is the target for hormonal inhibition of spermatogonial differentiation, we will transplant tubules between jsd mice and AR-deficient jsd mice and use cell-type specific elimination of an AR gene with loxP sites using Cre-recombinase driven by promoters specific for the different somatic cells. (IV) To identify the responsible gene, we will differentially screen for candidate hormone-regulated genes in the target cell of jsd mice using microarrays. A good candidate gene must have its level changed by GnRH antagonist in one direction and by T in the opposite direction. Elucidation of the mechanism of this spermatogonial """"""""arrest"""""""" and its reversal in the jsd mouse could apply to cases of genetically determined male infertility. Because of its remarkable similarity to the failure of spermatogonial differentiation in toxicant-treated and aging rats, these results could also apply to azoospermia induced by reproductive toxicants and the decline in spermatogenesis with aging.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040397-03
Application #
6707997
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Rankin, Tracy L
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$270,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Drumond, Ana Luiza; Weng, Connie C; Wang, Gensheng et al. (2011) Effects of multiple doses of cyclophosphamide on mouse testes: accessing the germ cells lost, and the functional damage of stem cells. Reprod Toxicol 32:395-406
Shetty, Gunapala; Porter, Karen L; Zhou, Wei et al. (2011) Androgen suppression-induced stimulation of spermatogonial differentiation in juvenile spermatogonial depletion mice acts by elevating the testicular temperature. Endocrinology 152:3504-14
Zhou, Wei; Wang, Gensheng; Small, Christopher L et al. (2011) Gene expression alterations by conditional knockout of androgen receptor in adult Sertoli cells of Utp14b jsd/jsd (jsd) mice. Biol Reprod 84:400-8
Wang, Gensheng; Shao, Shan H; Weng, Connie C Y et al. (2010) Hormonal suppression restores fertility in irradiated mice from both endogenous and donor-derived stem spermatogonia. Toxicol Sci 117:225-37
Zhou, Wei; Wang, Gensheng; Small, Christopher L et al. (2010) Gene expression alterations by conditional knockout of androgen receptor in adult sertoli cells of Utp14b(jsd/jsd) (jsd) mice. Biol Reprod 83:759-66
Wang, Gensheng; Weng, Connie C Y; Shao, Shan H et al. (2009) Androgen receptor in Sertoli cells is not required for testosterone-induced suppression of spermatogenesis, but contributes to Sertoli cell organization in Utp14b jsd mice. J Androl 30:338-48
Shetty, Gunapala; Shao, Shan H; Weng, Connie C Y (2008) p53-dependent apoptosis in the inhibition of spermatogonial differentiation in juvenile spermatogonial depletion (Utp14bjsd) mice. Endocrinology 149:2773-81
Zhao, Ming; Rohozinski, Jan; Sharma, Manju et al. (2007) Utp14b: a unique retrogene within a gene that has acquired multiple promoters and a specific function in spermatogenesis. Dev Biol 304:848-59
Bolden-Tiller, Olga U; Chiarini-Garcia, Helio; Poirier, Christophe et al. (2007) Genetic factors contributing to defective spermatogonial differentiation in juvenile spermatogonial depletion (Utp14bjsd) mice. Biol Reprod 77:237-46

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