Translational Control in Oogenesis and Embryogenesis

原发性卵巢功能不全（POI）是卵巢功能不全的一部分，从不孕症到不孕症， 高FSH水平导致45岁之前的早期绝经，影响5-10%的女性。A型糖尿病的病因 大多数病例仍未得到诊断，许多原因将是遗传性的。我们发现了一个止损点 一个POI家族中eIF 4 ENIF 1的突变。该基因是mRNA翻译控制的核心， 卵子发生，似乎也在胚胎发生中发挥关键作用。我们的小鼠模型重现了人类 杂合子不育是由于早期卵泡丢失和纯合子胚胎发生失败。我们将 在小鼠模型中通过Eif 4 enif 1的棱镜检查翻译调节。具体目标1检查 通过发现卵泡丢失的时间和原因，研究Eif 4 enif 1停止获得突变的不孕症病因。 具体目标1还检查了使用体外受精（IVF）失败的胚胎发生的遗传学。具体 目的2研究卵巢中翻译起始和阻遏的时间和空间调控， 免疫组化和Western blot。特异性Aim 3探针Eif 4 enif 1中的差异mRNA翻译 与野生型相比，停止获得突变卵巢，以鉴定卵母细胞关键的mRNA种类 发展进程这项工作涉及研究所的优先事项，以了解遗传基础， 不孕症，并为早期胚胎发育的研究开发了一种新的工具。 相关性：翻译监管是一条未得到充分研究的途径，它构成了监管的核心。 控制卵母细胞和胚胎发育。剖析对翻译至关重要的基因和途径 监管将成为了解基因检测期间发现的基因突变及其影响的基础 在不孕症中的潜在因果作用。对导致不育的基因有了更深入的了解， 保持生育能力，并在为时已晚之前为这些妇女创造有针对性的治疗方案。

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.