Large gaps remain in our understanding of the molecular mechanisms that activate the growth of ovarian primordial follicles, the first step of a process (follicular maturation) that culminates in egg release (ovulation). We will systematically dissect the key signalling pathway that requires the forkhead transcription factor FoxO3 to regulate the delicate balance between primordial follicle preservation and activation. Our goals are to: 1) exploit genetic approaches to confirm the importance of key genes encoding pathway components and to uncover their specific roles in primordial follicle activation; 2) identify and validate physiologic targets of FoxO3 by comparing transcriptional profiles of ovaries derived from FoxO3-deficient and wild-type control females; 3) characterize changing expression patterns, subcellular localization, and activation status of pathway components in primordial and early growing follicles, using a combination of antibody probes, pharmacologic agents, and in vitro culture, thereby revealing essential details of how this pathway regulates primordial follicle activation; 4) screen for genetic variants or mutations of the FOXO3A gene--the only known potent suppressor of primordial follicle activation-in women with premature ovarian failure (a condition associated with the depletion of primordial follicles early in life), thereby testing the hypothesis that an increased rate of follicle activation is one cause of premature ovarian failure. An improved understanding of this pathway will lead to insights into the biological and genetic basis of female infertility, create significant opportunities to develop predictive genetic tests for hereditary forms of female infertility, and may some day lead to the development of improved contraceptives that preserve the primordial follicle pool. These studies could also lead directly to prognostic tests to identify women predisposed to develop premature ovarian failure.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-C (02))
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Taymans, Susan
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Ezzati, M Max; Baker, Michael D; Saatcioglu, Hatice D et al. (2015) Regulation of FOXO3 subcellular localization by Kit ligand in the neonatal mouse ovary. J Assist Reprod Genet 32:1741-7
Aloisio, Gina M; Nakada, Yuji; Saatcioglu, Hatice D et al. (2014) PAX7 expression defines germline stem cells in the adult testis. J Clin Invest 124:3929-44
Baker, M D; Ezzati, M; Aloisio, G M et al. (2014) The small GTPase Rheb is required for spermatogenesis but not oogenesis. Reproduction 147:615-25
Harrison, Steven M; Campbell, Ian M; Keays, Melise et al. (2013) Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Am J Med Genet A 161A:2487-94
Tarnawa, Edward D; Baker, Michael D; Aloisio, Gina M et al. (2013) Gonadal expression of Foxo1, but not Foxo3, is conserved in diverse Mammalian species. Biol Reprod 88:103
Liu, Zhilin; Castrillon, Diego H; Zhou, Wei et al. (2013) FOXO1/3 depletion in granulosa cells alters follicle growth, death and regulation of pituitary FSH. Mol Endocrinol 27:238-52
Goertz, Meredith J; Wu, Zhuoru; Gallardo, Teresa D et al. (2011) Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis. J Clin Invest 121:3456-66
Sullivan, Shannon D; Castrillon, Diego H (2011) Insights into primary ovarian insufficiency through genetically engineered mouse models. Semin Reprod Med 29:283-98
Strauss, Tamara J; Castrillon, Diego H; Hammes, Stephen R (2011) GATA-like protein-1 (GLP-1) is required for normal germ cell development during embryonic oogenesis. Reproduction 141:173-81
John, George B; Shidler, Meredith J; Besmer, Peter et al. (2009) Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation. Dev Biol 331:292-9

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