Translational Control in Oogenesis and Embryogenesis

原发性卵巢功能不全(POI)是一系列卵巢功能障碍的一部分，包括不孕不育和 高FSH水平至45岁前绝经早期，影响5%-10%的女性。急性胰腺炎的病因学 大多数病例仍未得到诊断，许多原因将是遗传的。我们发现了一个止损收益 一个POI家系eIF4ENIF1基因突变该基因是mRNA翻译控制的核心。 卵子发生，似乎也在胚胎发生中起着关键作用。我们的小鼠模型重现了人类 纯合子早期卵泡丢失和胚胎发育失败导致的杂合子不孕不育。我们会 通过Eif4enif1的棱镜在小鼠模型中检测翻译调节。《特定目标1》考查 Eif4enif1不孕症的病因学通过发现卵泡丢失的时间和原因来停止增益突变。 特殊目的1还检查了使用体外受精(IVF)失败的胚胎发生的遗传学。特定的 目的2研究卵巢翻译启动和抑制的时间和空间调节。 免疫组织化学和Western印迹分析。特异性靶标3探查Eif4enif1中的差异mRNA翻译 卵巢Stop Gain突变卵巢与野生型的比较以鉴定对卵母细胞至关重要的mRNA物种 发育进程。这项工作解决了研究所了解遗传病遗传基础的优先事项 并为研究早期胚胎发育提供了一种新的工具。 相关性：翻译调控体现了一条研究不足的途径，这构成了调控的症结所在 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 监管将成为理解在基因检测过程中发现的基因突变及其 不孕不育的潜在原因。对导致不孕不育的基因的更多了解创造了 在为时已晚之前，保持生育能力，并为这些妇女创造有针对性的治疗选择。

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.