Germ cells carry the history of our generation(s) and are unique in their biology as well as of utmost importance in propagation and causation of genetic disorders. Their uniqueness is also reflected in unique mechanisms and molecules that govern their differentiation and growth. We are particularly interested in understanding transcriptional regulation of ovarian 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. These transcription factors are necessary to drive oocyte growth, and synthesis of maternal effect genes that determine early embryogenesis and are likely involved in setting of epigenetic marks. 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 and Sohlh2 are basic helix-loop-helix transcriptional regulators that suppress primordial follicle activation (PFA), and Sohlh1 and Sohlh2 deletions cause rapid PFA and oocyte loss. LHX8, a highly conserved LIM homeodomain protein, is located downstream of SOHLH1 and SOHLH2, and also represses primordial follicle activation. SOHLH1, SOHLH2 and LHX8 are uniquely expressed in the germline, and their deficiency affects gonadal development. We have a conditional knockout of Lhx8 and other tools to study how this pathway regulates postnatal folliculogenesis. We are currently using Lhx8 as a model system to understand oocyte-specific repression of follicle activation. Conditional deficiency of Lhx8 in oocytes of primordial follicles, leads to massive primordial follicle activation and premature oocyte depletion. We are studying the Lhx8 cross talk with the PI3K-AKT/mTORC1 dependent pathways as well as novel, PI3K-AKT/mTORC1 independent pathways. We are also studying the importance of oocyte-specific pathways at different stages of folliculogenesis and ovarian development, as well as promoters that LHX8 directly binds and regulates.
Our laboratory also discovered HORMAD1, a major meiotic checkpoint in both male and female germline development. Unlike other meiotic checkpoints, HORMAD1 deficiency does not affect female germline nor gonadal development, as expected from a true checkpoint. Unlike other checkpoints, the ovaries in these animals are completely normal, with normal ovulation but absolute infertility due to embryo aneuploidy. Our findings show that meiosis and oocyte differentiation and survival are independent of each other, and we are studying the embryonic pathways of oocyte activation and differentiation.
In addition to uncovering mechanisms of oogenesis, we are interested in exploiting tissue-specific pathways to modulate fertility and reproductive life span and measure ovarian reserves. We are specifically interested to identify novel biomarkers of primordial follicle reserves as well as tissue-specific targets to control reproductive life span.