Regulation of Fetal Ovarian Development by GATA4

描述（由申请人提供）：在胚胎发生和胎儿生长期间影响卵巢正常发育的扰动可导致生殖障碍，如不孕症、卵巢早衰或卵巢癌。然而，关于正常胎儿卵巢发育的因素和细胞事件知之甚少。最近的观察表明转录因子GATA4是胎儿卵巢发育的调节因子，但其确切功能尚不清楚。我们研究的长期目标是更好地了解控制哺乳动物胎儿卵巢发育和分化的细胞和分子事件。本提案将验证的中心假设是GATA4通过调节细胞周期进程来控制胎儿卵巢体细胞分化。为了验证我们的假设，提出了以下具体目标：(1)确定GATA4如何调节胎儿卵巢体细胞增殖。(2)确定胎儿卵巢体细胞分化过程中GATA4是否与TGF¿信号通路相互作用。研究人员将利用一种独特的转基因小鼠模型，在该模型中，GATA4在胎儿卵巢体细胞中被特异性删除，并利用分子方法评估GATA4与细胞周期程序的相互作用，以及TGF¿介导的对胎儿卵巢体细胞分化的控制。这一建议具有创新性，因为它提供了对调节胎儿卵巢发育的细胞和分子事件的见解，并且新颖，因为它将确定哺乳动物胎儿卵巢体细胞中GATA4的功能。确定GATA4在胎儿卵巢发育中的作用将为了解女性生殖疾病（如卵巢癌）提供重要的见解，因为在卵巢肿瘤中已经观察到GATA4的异常表达。

DESCRIPTION (provided by applicant): Perturbations affecting normal development of the ovaries during embryogenesis and fetal growth can lead to reproductive disorders such as infertility, premature ovarian failure, or ovarian cancer. However, little is known about the factors and cellular events underlying normal fetal ovarian development. Recent observations indicate that the transcription factor GATA4 is a regulator of fetal ovarian development, however its exact function is not known. The long-term goal of our research is to obtain a better understanding of the cellular and molecular events controlling development and differentiation of the mammalian fetal ovaries. The central hypothesis that will be tested in this proposal is that GATA4 controls fetal ovarian somatic cell differentiation by regulating cell cycle progression. To test our hypothesis the following specific aims are proposed: (1) Determine how GATA4 regulates fetal ovarian somatic cell proliferation. (2) Determine if GATA4 interacts with the TGF¿ signaling pathway during fetal ovarian somatic cell differentiation. The proposed aims will be accomplished by using a unique transgenic mouse model in which GATA4 is specifically deleted in fetal ovarian somatic cells, and by using molecular approaches to assess GATA4 interaction with the cell cycle program, and TGF¿ mediated control of fetal ovarian somatic cell differentiation. This proposal is innovative because it provides insight into the cellular and molecular events regulating fetal ovarian development, and novel because it will identify a function for GATA4 in mammalian fetal ovarian somatic cells. Determining the role of GATA4 in fetal ovarian development will offer important insight into female reproductive disease such as ovarian cancer, as abnormal GATA4 expression has been observed in ovarian tumors. PUBLIC HEALTH RELEVANCE: Any perturbations in the process of fetal ovarian development and differentiation can lead to a range of severe adverse consequences in adulthood, including infertility and ovarian cancer. Ovarian cancer is the most lethal gynecological malignancy in women because it often is detected at a late stage when tumor growth has spread to other tissues. A gene abnormally expressed in ovarian tumors is Gata4. This research aims to identify the role of Gata4 during fetal ovarian development, which will provide important information about the mechanism controlling early fetal ovarian somatic cell proliferation, and is essential to obtain insight into female reproductive disorders and disease.