Infertility afflicts about 10% of women between the ages of 15 and 44 and can be triggered by a wide range of conditions, including disease, therapeutic treatment for disease, toxins, and age. Although these conditions often impair fertility by affecting oocyte quality, our limited understanding of how the oocyte communicates with its environment has hampered the development of effective therapeutic strategies. Oocyte development depends absolutely on contact with somatic granulosa cells in the ovarian follicle. When communication with the granulosa cells is impaired, functional oocytes are not produced. This intercellular communication is mediated through long cytoplasmic filaments, termed transzonal projections (TZPs), that extend from the granulosa cells and penetrate the thick extracellular coat (zona pellucida) that surrounds the germ cell to reach the oocyte plasma membrane. Although TZPs are the sole means by which the granulosa cells and growing oocytes physically communicate, no research has addressed when or how these unique structures form. Our preliminary data indicates that the number of TZPs increases substantially during the growth phase of oogenesis. Strikingly, the granulosa cells adjacent to growing oocytes express highly conserved activators of filopodial growth, and the oocyte-derived TGF? superfamily member, GDF (growth-differentiation factor)-9 increases the number of TZPs projecting from the surrounding granulosa cells. We propose that TZPs are specialized filopodia that are dynamically elaborated from the granulosa cells surrounding growing oocytes and that TZP formation is regulated by TGF? superfamily members secreted by the oocyte whose effect is transduced through SMAD4-dependent signaling in the granulosa cells. Using a combination of genetic and in vitro approaches, we will determine whether GDF-SMAD4 signaling regulates (i) expression and/or localization of filopodial assembly factors, (ii) TZP formation and (iii) gap junctional coupling between the oocyte and the granulosa cells. This new model of TZP formation differs fundamentally from current understanding because it emphasizes that the physical lines of communication that link the oocyte to its somatic environment are dynamic structures, and therefore are subject to genetic and epigenetic influences. It will establish a new paradigm for understanding how ? by influencing TZP formation, function or stability ? disease and environmental conditions can compromise oocyte quality. It will also provide a novel conceptual platform for designing and developing new strategies to rescue fertility in women and will help propel new efforts to derive functional oocytes from pluripotent stem cells.
New approaches to understanding how the developing oocyte communicates with the somatic cells that constitute its microenvironment are essential to overcome the damaging effects of environmental conditions including age, disease, and environmental hazards on the oocyte. The research proposed here tests a radically new model for how this communication is established, and differs fundamentally from current understanding because it emphasizes that the physical lines of communication that link the oocyte to its somatic environment are dynamic structures. It will provide a novel conceptual platform for developing new strategies to rescue fertility in women.
|Clarke, Hugh J (2018) Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle. Wiley Interdiscip Rev Dev Biol 7:|
|El-Hayek, Stephany; Yang, Qin; Abbassi, Laleh et al. (2018) Mammalian Oocytes Locally Remodel Follicular Architecture to Provide the Foundation for Germline-Soma Communication. Curr Biol 28:1124-1131.e3|