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.
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.
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