We are interested in understanding transcriptional regulation of follicle activation and oocyte survival. Early stages of ovarian follicle formation, beginning with the breakdown of germ cell cysts, formation of primordial follicles and transition to primary and secondary follicles, are critical in determining the reproductive life span and fertility. Transcription of numerous germ cell specific genes, necessary and essential for follicular development, is initiated during these early stages of follicle formation. We discovered novel germ cell specific transcriptional regulators Sohlh1, Sohlh2, Lhx8, and Nobox. We also discovered that mutations in oocyte- specific transcriptional regulators such as Nobox and Figla associate with premature ovarian failure, emphasizing the importance of these pathways to women's health. Sohlh1 is a basic helix-loop-helix transcriptional regulator that suppresses primordial follicle activation (PFA), and Sohlh1 depletion causes rapid PFA and oocyte loss. LHX8, a highly conserved LIM homeodomain protein, is located downstream of SOHLH1, and also represses primordial follicle activation. SOHLH1 and LHX8 are uniquely expressed in the germline, and their deficiency affects gonadal development. We developed a conditional knockout of Lhx8 and other tools to study how this pathway regulates postnatal folliculogenesis. We will use Lhx8 as a model system to understand oocyte-specific repression of follicle activation.
In Specific Aim 1 we will determine mechanisms whereby LHX8 suppresses primordial follicle activation. Conditional deficiency of Lhx8 in oocytes of primordial follicles, leads to massive primordial follicle activation and premature oocyte depletion. We hypothesize that Lhx8 controls PFA via cross talk with the PI3K-AKT/mTORC1 dependent pathways, and by regulating novel secreted factors.
In Specific Aim 2, we hypothesize that oocyte-specific pathways are important not only in the developing ovary but also adult ovary and at different stages of folliculogenesis.
In Specific Aim 3, we hypothesize that LHX8 directly binds promoters of oocyte-specific regulators essential for follicle activation. Our previous and current studies focus on oocyte specific mechanisms that suppress follicular activation and oocyte loss. We identified unique regulators of follicle activation and oocyte survival, yet mechanisms of their action remain unknown. We will utilize our unique animal models to elucidate these mechanisms. Our studies are likely to identify novel biomarkers of primordial follicle reserves as well as tissue-specific targets to control reproductive life span.

Public Health Relevance

We identified master genes that will give us insight into the causes of ovarian failure, infertility and early menopause. Understanding regulatory pathways controlled by master genes may not only help us with identification of genes important for premature ovarian failure, infertility, ovarian tumors, and embryo losses, but will provide us with tissue-specific targets to regulate human fertility.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HD044858-07
Application #
8743087
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ramaswamy, Suresh; Razack, Bibi S; Roslund, Rachel M et al. (2014) Spermatogonial SOHLH1 nucleocytoplasmic shuttling associates with initiation of spermatogenesis in the rhesus monkey (Macaca mulatta). Mol Hum Reprod 20:350-7
Lechowska, Agnieszka; Bilinski, Szczepan; Choi, Youngsok et al. (2011) Premature ovarian failure in nobox-deficient mice is caused by defects in somatic cell invasion and germ cell cyst breakdown. J Assist Reprod Genet 28:583-9
Ahn, Hyo Won; Morin, Ryan D; Zhao, Han et al. (2010) MicroRNA transcriptome in the newborn mouse ovaries determined by massive parallel sequencing. Mol Hum Reprod 16:463-71
Krotz, Stephan P; Ballow, Daniel J; Choi, Youngsok et al. (2009) Expression and localization of the novel and highly conserved gametocyte-specific factor 1 during oogenesis and spermatogenesis. Fertil Steril 91:2020-4
Choi, Youngsok; Yuan, Daniel; Rajkovic, Aleksandar (2008) Germ cell-specific transcriptional regulator sohlh2 is essential for early mouse folliculogenesis and oocyte-specific gene expression. Biol Reprod 79:1176-82
Choi, Youngsok; Ballow, Daniel J; Xin, Yun et al. (2008) Lim homeobox gene, lhx8, is essential for mouse oocyte differentiation and survival. Biol Reprod 79:442-9
Qin, Yingying; Zhao, Han; Kovanci, Ertug et al. (2008) Analysis of LHX8 mutation in premature ovarian failure. Fertil Steril 89:1012-4
Zhao, Han; Rajkovic, Aleksandar (2008) MicroRNAs and mammalian ovarian development. Semin Reprod Med 26:461-8
Zhao, Han; Chen, Zi-Jiang; Qin, Yingying et al. (2008) Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet 82:1342-8
Zhao, Han; Qin, Yingying; Kovanci, Ertug et al. (2007) Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertil Steril 88:1474-6

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