Translational Control in Oogenesis and Embryogenesis

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Primary ovarian insufficiency (POI) is part of the continuum of ovarian dysfunction ranging from infertility with a high FSH level to early menopause before age 45 years, and affects 5-10% of women. The etiology in a majority of cases remains undiagnosed, and many of the causes will be genetic. We identified a stop gain mutation in eIF4ENIF1 in a family with POI. The gene is at the heart of mRNA translational control in oogenesis and also appears to play a critical role in embryogenesis. Our mouse model recapitulates human infertility in heterozygotes through early follicle loss and failed embryogenesis in homozygotes. We will examine translation regulation through the prism of Eif4enif1 in a mouse model. Specific Aim 1 examines the etiology of infertility in Eif4enif1 stop gain mutations by discovering the timing and cause of follicle loss. Specific Aim 1 also examines the genetics of failed embryogenesis using in vitro fertilization (IVF). Specific Aim 2 examines the temporal and spatial regulation of translation initiation and repression in ovaries using immunohistochemistry and Western blot. Specific Aim 3 probes differential mRNA translation in the Eif4enif1 stop gain mutation ovaries compared to wild type to identify the mRNA species critical for oocyte developmental progression. The work addresses the Institute’s priorities to understand the genetic basis of infertility and develops a new tool for the study of early embryo development. Relevance: Translation regulation exemplifies an understudied pathway that forms the crux of regulatory control in oocyte and embryo development. Dissecting the genes and pathways critical for translation regulation will form the basis to understand genetic mutations identified during genetic testing and their potential causal role in infertility. A greater understanding of the genes causing infertility creates the potential to preserve fertility and create targeted treatment options for these women before it is too late.