The fundamental relationships established between somatic cells and oocytes within germline cysts and primordial follicles during ovary development provide the framework for successful oocyte survival, maturation, and ultimate release upon ovulation. A long-term goal of our work is to discover the pathways and factors that facilitate oocyte-somatic cell communication during ovary development and early follicle formation. This issue is critical for us to develop the means to cultivate oocyte health during follicle development and maturation to ultimately preserve genetic transfer and species survival. The fundamental hypothesis guiding this proposal is that Iroquois homeobox transcription factors, Irx3/5, which are tightly regulated by ?catenin, coordinate somatic cell-oocyte communication to promote oocyte survival and early stages of follicle maturation.
In AIM 1, inducible mouse models will be used to knockout and knock-in gonad Irx3/5 activity to identify their critical juncture of temporal and spatial expression that regulates communication between somatic cells and the oocyte in germline cysts and primordial follicles to promote oocyte health and survival. Then in AIM 2, we will investigate the temporal and spatial transcriptional regulation of Irx3/5 by ?catenin in somatic and germ cells and the functional outcome of this pathway by evaluating whether re-introduction of Irx3 expression can rescue the germ cell death phenotype in ?catenin-mutant ovaries. Successful completion of these aims will uncover a novel pathway, ?catenin-Irx3/5, in the control of oocyte-granulosa cell communication whose disruption may contribute to causes of infertility and premature ovarian failure.
Women without functional ovaries, or those that experience premature ovarian failure (POF) are infertile and require significant intervention to maintain systemic health. Most causes of POF remain undiagnosed;however, a critical feature is oocyte death, which depends on intimate contacts between the oocyte and granulosa cells initiated within the fetal ovary. Successful completion of these aims will expose essential components of somatic-germ cell contacts to maintain follicle health so that new treatment or preventative modalities may be developed for women suffering POF.
|Fu, Anqi; Oberholtzer, Sydney M; Bagheri-Fam, Stefan et al. (2018) Dynamic expression patterns of Irx3 and Irx5 during germline nest breakdown and primordial follicle formation promote follicle survival in mouse ovaries. PLoS Genet 14:e1007488|
|Jorgensen, Joan S (2013) Defining the neighborhoods that escort the oocyte through its early life events and into a functional follicle. Mol Reprod Dev 80:960-76|