Ovarian-specific transcription networks regulated by the TFIID subunit TAF4b

描述(申请人提供)：哺乳动物的卵巢是独一无二的，因为它的繁殖寿命受到卵母细胞数量和质量的限制。卵母细胞是从有限的原始卵泡池中招募的，这些原始卵泡通常在成年中期从卵巢中耗尽。如果这个池的调节受到干扰，卵巢的生殖能力就会受到影响。先前对TAF4b缺陷小鼠卵巢的描述揭示了几种生殖缺陷，这些缺陷共同导致女性不孕。通过对TAF4b基因缺失雌性幼鼠的动情周期、卵巢病理和基因表达变化的评估，我们已经确定TAF4b缺失雌性小鼠表现出过早的生殖衰老。根据这些初步数据，我们假设TAF4b调控卵母细胞特异性基因的转录，这是适当维持原始卵泡池和成人健康生育所需的卵母细胞质量所必需的。这项研究的目的是破译TAF4b在调节正常原始卵泡存活和卵巢衰老中的基本细胞和分子机制。为了实现我们的目标，我们提出了三个相关但不重叠的具体目标：1)确定新生儿原始卵泡过度缺乏TAF4b的细胞机制；2)阐明TAF4b对染色体突触、分离和减数分裂的调节；以及3)确定TAF4b依赖的卵子质量调节的机制基础。由于TAF4b对小鼠原始卵泡发育的正常调节是必需的，人类卵巢中TAF4b介导的事件的解除可能是许多女性生育缺陷的潜在原因，包括原因不明的不孕症(占女性不孕症的10%)和卵巢早衰(在全球1%的女性人口中观察到)。事实上，最近对人类生育能力的研究表明，人类TAF4b基因的序列及其适当的表达对于促进女性健康的卵母细胞质量和卵巢老化至关重要。因此，阐明TAF4b在出生后卵母细胞发育中的关键细胞和分子机制，不仅可以识别哺乳动物卵巢生物学的基本生物学原理，还可以解释女性生殖健康疾病的病因，如原发卵巢功能不全。这些研究将增加我们的基本知识，使我们能够保存和/或提高后代妇女的卵子质量。 公共卫生相关性：原发性卵巢功能不全(POI)，也被称为卵巢早衰，影响全球约1%的妇女。我们的初步数据表明，TAF4b调节的过程涉及卵巢中关键基因的表达，这些基因是维持原始卵泡池和健康卵巢衰老所必需的。由于最近对人类生育能力的研究已经独立地将TAF4b功能与适当的卵巢衰老和卵母细胞质量联系在一起，因此本文提出的揭示TAF4b调节卵巢衰老机制的工作将揭示女性生殖功能的基本生物学原理，这些功能是健康生育所必需的。这些研究可能导致先进的诊断和治疗工具，以更好地解决和管理女性不孕症。

DESCRIPTION (provided by applicant): The mammalian ovary is unique in that its reproductive lifespan is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during mid-adult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. Previous characterization of TAF4b-deficient mouse ovaries revealed several reproductive deficits that collectively result in female infertility. By assessing estrous cyclicity, ovarian pathology and gene expression changes in young TAF4b-deficient female mice, we have determined that TAF4b-null females exhibit premature reproductive senescence. Based on these preliminary data, we hypothesize that TAF4b regulates the transcription of oocyte-specific genes required for proper maintenance of the primordial follicle pool and oocyte quality that is required for healthy fertility in the adult. The objective of the proposed research is to decipher fundamental cellular and molecular mechanisms of TAF4b in the regulation of proper primordial follicle survival and ovarian aging. To accomplish our goals we propose three related, but non-overlapping specific aims to: 1) determine the cellular mechanisms of excessive neonatal TAF4b-deficient primordial follicle attrition; 2) elucidate the TAF4b regulation of chromosome synapsis, segregation and meiosis; and 3) determine the mechanistic basis of TAF4b-dependent regulation of oocyte quality. Since TAF4b is required for normal regulation of primordial follicle development in the mouse, deregulation of TAF4b-mediated events in human ovaries may be an underlying cause of a number of female fertility defects including unexplained infertility, which accounts for 10% of female infertility, and premature ovarian failure, which is observed in 1% of the female population worldwide. In fact, recent studies of human fertility have implicated the sequence of the human TAF4b gene and its proper expression as being critical for promoting healthy oocyte quality and ovarian aging in women. Thus, elucidating the critical cellular and molecular mechanisms of TAF4b in postnatal oocyte developmental will both identify fundamental biological principles of mammalian ovarian biology as well as illuminate the etiology of female reproductive health disorders in women such as primary ovarian insufficiency. These studies will increase our basic knowledge which may allow us to preserve and/or enhance oocyte quality in women of future generations. PUBLIC HEALTH RELEVANCE: Primary ovarian insufficiency (POI), also referred to as premature ovarian failure, affects approximately 1% of women worldwide. Our preliminary data implicate TAF4b-regulated processes in the expression of critical genes in the ovary that are required for the maintenance of the primordial follicle pool and healthy ovarian aging. As recent studies of human fertility have independently linked TAF4b functions to proper ovarian aging and oocyte quality, the work proposed here to uncover the mechanisms of TAF4b in regulating ovarian aging will reveal fundamental biological principles underlying reproductive functions in women that are required for healthy fertility. These studies may lead to advanced diagnostic and therapeutic tools to better address and manage female infertility.