Impacts of Genetic and Environmental Factors on Reproductive Organ Development

1.确定胎儿性腺中体细胞谱系的来源，并研究它们如何获得器官特异性身份 本项目确定转录因子RUNX 1是一种新的颗粒细胞命运的调节因子。性腺的身份取决于促睾丸和促卵巢力量之间的平衡。很明显，睾丸的命运决定过程是线性和顺序的：去除一个最重要的调节因子（即SRY或SOX 9）具有多米诺骨牌效应，导致完全的睾丸到卵巢性逆转。然而，在小鼠卵巢中并非如此，在小鼠卵巢中没有单基因丢失/突变导致完全的卵巢-睾丸性逆转。这种性别差异意味着卵巢中有一个多组分系统在起作用。在这项研究中，我们意外地发现了转录因子RUNX 1作为一个新的球员在卵巢的命运指定过程。RUNX 1因其在造血细胞分化中的关键作用及其与人类急性髓性白血病的联系而闻名。然而，在卵巢中，RUNX 1通过与另一个卵巢转录因子FOXL 2的相互作用来维持卵巢的身份。使用小鼠遗传模型和转录组学和全基因组染色质方法的组合，我们发现RUNX 1作为抗睾丸因子的功能，拮抗胚胎小鼠卵巢中睾丸程序的出现。我们还发现，RUNX 1是丰富的胎儿卵巢的各种脊椎动物物种，包括人类，山羊，虹鳟鱼和海龟，这表明其在卵巢分化的保守作用。卵巢分化的缺陷对女性的生殖结果有着可怕的后果，从性逆转到不孕，这些缺陷背后的分子机制往往没有被确定。我们的研究结果为卵巢分化的基因组控制提供了新的见解，并为鉴定有助于卵巢正常功能和病理学的新型转录因子和顺式签名铺平了道路。鉴于卵巢细胞分化障碍与多囊卵巢综合征（PCOS）、卵巢早衰和卵巢癌等卵巢疾病有关，因此颗粒细胞发育的主题至关重要。 2.调查子宫内暴露于内分泌干扰物对胎儿生殖器官发育的影响及其对成年生育能力的持续影响 胎儿生殖器官的形成依赖于类固醇激素和信号分子之间复杂的相互作用，因此使这一过程成为内分泌干扰物的主要目标。已知模拟或干扰类固醇激素和信号分子作用的化学品或化合物对胎儿生殖器官形成具有有害影响，并在受影响动物成年后对生育力产生长期影响。砷是一种在地下水和食品中发现的人类致癌物质，已知会影响生殖系统。小鼠胚胎暴露于砷会导致卵巢和生殖道的癌症发展。为探讨妊娠期砷暴露对个体成年后的长期影响，本研究用人类相关剂量的饮用水对孕鼠进行砷暴露。当一些暴露的男性胎儿发育到成年时，他们变得肥胖并出现代谢问题，如葡萄糖耐受不良。我们的研究结果表明，在子宫内砷暴露对代谢的潜在影响。

1. Identify the sources of somatic cell lineages in the fetal gonads and investigate how they acquire their organ-specific identities This project identifies the transcription factor RUNX1 s a novel regulator of granulose cell fate The identity of the gonads hinges upon the balance between pro-testis and pro-ovary forces. It is clear that the fate determination process of the testis is linear and sequential: Removal of one of the top regulators (i.e. SRY or SOX9) has a domino effect that lead to complete testis to ovary sex-reversal. However, this is not the case in the mouse ovary, where no single-gene loss/mutation results in a complete ovary-to-testis sex-reversal. This sex difference implies a multi-component system in action in the ovary. In this study, we discovered unexpectedly the transcription factor RUNX1 as a new player in the fate specification process of the ovary. RUNX1 is known for its critical role in the differentiation of hematopoietic cells and its link to acute myeloid leukemia in humans. In the ovary, however, RUNX1 acts to maintain the identity of the ovary through an interplay with another ovarian transcription factor FOXL2. Using a combination of mouse genetic models and transcriptomic and genome-wide chromatin approaches, we uncovered RUNX1 functions as anti-testis factor that antagonizes the appearance of the testis program in the fetal mouse ovary. We also found that RUNX1 is enriched in the fetal ovary of various vertebrate species including humans, goats, rainbow trout, and turtles, suggesting its conserved role in ovarian differentiation. Defects in ovarian differentiation have dire consequences on reproductive outcomes of women, from sex-reversal to infertility, and the molecular mechanisms behind these defects are often not identified. Our findings provide new insights into the genomic control of ovarian differentiation, and pave the way for the identification of novel transcription factors and cis-signatures contributing to the normal functions and pathology of the ovary. The topic of granulosa cell development is fundamentally important, given that disorders in ovarian cell differentiation are implicated in ovarian diseases such as polycystic ovary syndrome (PCOS), premature ovarian failure, and ovarian cancers. 2. Investigate the effects of in utero exposure to endocrine disruptors on the development of fetal reproductive organs and its lingering impacts on fertility in adulthood Formation of fetal reproductive organs relies on an intricate interaction between steroid hormones and signaling molecules, therefore making this process a prime target of endocrine disruptors. Chemicals or compounds that mimic or interfere with the action of steroid hormone and signaling molecules are known to have detrimental impacts on fetal reproductive organ formation and long-term impacts on fertility when the affected animals reach adulthood. Arsenic, a human carcinogen found in underground water and food products, is known to impact reproductive systems. Exposure of mouse embryos to arsenic led to cancer development in the ovary and reproductive tracts. To investigate whether arsenic exposure during gestation has a long term impact on the individuals when they reach adulthood, we exposed pregnant mice with human relevant dose of arsenic in the drinking water. When some of the exposed male fetuses are allowed to develop to adulthood, they became obese and developed metabolic problems such as glucose intolerance. Our findings demonstrate a potential impact of in utero arsenic exposure on metabolism.