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，并调查它们如何获得器官特异性身份 本项目确定了转录因子RUNX1，S，一种新的颗粒细胞命运调节因子，性腺的识别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的和顺序的：移除顶级调控因子之一(即SRY或SOX9)会产生多米诺骨牌效应，导致完整的睾丸到卵巢的性别逆转。然而，在小鼠卵巢中情况并非如此，在那里没有单一基因丢失/突变导致完全的卵巢到睾丸的性别逆转。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RUNX1作为一个新的参与者参与了卵巢的命运指定过程。RUNX1因其在造血细胞分化中的关键作用以及与人类急性髓系白血病的联系而闻名。然而，在卵巢中，RUNX1通过与另一种卵巢转录因子FOXL2相互作用来维持卵巢的特性。使用小鼠遗传模型以及转录和全基因组染色质方法的组合，我们发现RUNX1作为抗睾丸因子在小鼠胚胎卵巢中对抗睾丸程序的出现。我们还发现RUNX1在各种脊椎动物的胚胎卵巢中都很丰富，包括人类、山羊、虹鲑鱼和海龟，这表明它在卵巢分化中起着保守的作用。卵巢分化缺陷对女性的生殖结局有可怕的后果，从性逆转到不育，这些缺陷背后的分子机制往往无法确定。我们的发现为卵巢分化的基因组调控提供了新的见解，并为鉴定有助于卵巢正常功能和病理的新的转录因子和顺式签名铺平了道路。考虑到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，颗粒细胞发育的主题是至关重要的。 2.研究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后生育的挥之不去的影响 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靶点。已知，模仿或干扰类固醇激素和信号分子的作用的化学品或化合物对胎儿生殖器官的形成有不利影响，并在受影响的动物成年后对生育能力产生长期影响。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。暴露在砷中的小鼠胚胎会导致卵巢和生殖道的癌症发展。为了研究怀孕期间的砷暴露是否会对成年后的个体产生长期影响，我们将怀孕小鼠暴露在饮用水中相应剂量的人类砷中。当一些被暴露的男性胎儿被允许发育到成年时，他们变得肥胖，并出现葡萄糖耐受等新陈代谢问题。我们的发现表明，宫内砷暴露对新陈代谢有潜在的影响。

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.