Greater than 99.9% of ovarian follicles undergo atresia during reproductive life and up to 75% of male germ cells degenerate during the spermatogenic process. Because the maintenance of optimal gonadal function depends on the survival of a limited number of selected follicles and healthy male germ cells, analysis of the hormonal control of gonadal cell demise is important for our understanding of gonadal physiology. We recently have demonstrated that apoptosis is the mechanism underlying follicle atresia and testis cell degeneration. We have devised a sensitive DNA 3'-end labeling autoradiographic method to quantitate apoptosis and have adapted an in situ method to identify the specific cell types involved in apoptosis. Using the rat as a model, we propose to document follicle and oocyte demise throughout ovarian development as well as to study the role of gonadotropins, GH and growth factors in the control of follicle atresia in vitro and in vivo. In the rat testis, we will analyze somatic and germ cell death during development. We will also elucidate the role of gonadotropins, androgens, GH and IGFI in the regulation of testis cell demise. The effect of elevated temperature on germ cell death will be analyzed in cryptorchid testis. To study the molecular mechanism underlying atresia, selected regulation of mRNA levels for different ovarian genes will be monitored during induction of apoptosis and a transgenic mouse model will be developed to suppress follicle atresia by targeted expression of the apoptosis suppressor gene, bcl-2, in the granulosa cells. Studies on the hormonal control of ovarian and testis cell death should provide a better understanding of gonadal physiology and future strategies for contraception in both sexes. Because different pathological conditions in the ovary (e.g., polycystic ovary syndrome and premature ovarian failure) and testis (e.g., oligo- and azoospermia) are likely due to aberrant regulation of apoptosis, the proposed studies may also provide new treatments for infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD031566-02
Application #
2204175
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1994-05-01
Project End
1998-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Stanford University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bae, Jeehyeon; Donigian, Jill R; Hsueh, Aaron J W (2003) Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis. J Biol Chem 278:5195-204
Chun, S Y; Bae, H W; Kim, W J et al. (2001) Expression of messenger ribonucleic acid for the antiapoptosis gene P11 in the rat ovary: gonadotropin stimulation in granulosa cells of preovulatory follicles. Endocrinology 142:2311-7
Bae, J; Hsu, S Y; Leo, C P et al. (2001) Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis. Apoptosis 6:319-30
Bae, J; Leo, C P; Hsu, S Y et al. (2000) MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 275:25255-61
Hsu, S Y; Kudo, M; Chen, T et al. (2000) The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 14:1257-71
Hsu, S Y; Hsueh, A J (2000) Tissue-specific Bcl-2 protein partners in apoptosis: An ovarian paradigm. Physiol Rev 80:593-614
Leo, C P; Hsu, S Y; Chun, S Y et al. (1999) Characterization of the antiapoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) and the stimulation of its message by gonadotropins in the rat ovary. Endocrinology 140:5469-77
Hsu, S Y; Hsueh, A J (1998) A splicing variant of the Bcl-2 member Bok with a truncated BH3 domain induces apoptosis but does not dimerize with antiapoptotic Bcl-2 proteins in vitro. J Biol Chem 273:30139-46
Hsu, S Y; Lin, P; Hsueh, A J (1998) BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Mol Endocrinol 12:1432-40
Leo, C P; Hsu, S Y; McGee, E A et al. (1998) DEFT, a novel death effector domain-containing molecule predominantly expressed in testicular germ cells. Endocrinology 139:4839-48

Showing the most recent 10 out of 29 publications