Unveil a Novel Pathway in Mammalian Ovary Development

描述（由申请人提供）：胚胎性腺的发育是决定成年个体生殖功能的第一个关键步骤。当性腺发育早期出现缺陷时，会出现性模糊、不孕症或肿瘤。这一建议的主要目的是了解性腺发育的基本过程，特别是关于卵巢的发育。哺乳动物卵巢的发育被认为是一个默认的途径，只有在没有sry定向的睾丸途径时才会出现。然而，我们最近的研究结果表明，卵巢的发育是一个活跃的信号级联反应的产物，涉及复杂的细胞-细胞相互作用和细胞命运决定。我们已经确定了两个新的分子，WNT4和卵泡抑素，在卵巢早期发育中起关键作用。Wnt4和卵泡抑素缺失小鼠在胚胎卵巢中具有相同的缺陷，包括睾丸特异性脉管系统的形成和生殖细胞的丢失。此外，我们发现卵泡抑素是WNT4调节脉管系统和生殖细胞发育的直接下游效应物。因此，我们假设WNT4和卵泡抑素是一个新的信号级联的组成部分，可以抑制睾丸特异性脉管系统，并维持卵巢发育过程中女性生殖细胞的存活。我们提出了三个具体目标：1)剖析WNT4的细胞内信号通路；2)了解卵泡抑素在卵巢发育中的调控作用；3)建立卵泡素阴性性腺睾丸特异性脉管系统的形成与生殖细胞损失的功能关系。通过结合转基因和器官培养技术，我们期望破译卵巢发育的分子和细胞途径，同时确定这些途径中易受遗传缺陷影响的关键成分。

DESCRIPTION (provided by applicant): Development of the embryonic gonad is the first critical step in determining the reproductive functionality of the adult individual. Sexual ambiguity, infertility, or neoplasia arises when defects occur in early gonad development. The main goal of this proposal is to understand the fundamental process of gonad development, especially as regards the development of the ovary. Development of the mammalian ovary is considered as a default pathway, arising only in the absence of Sry-directed testis pathway. However, our recent findings revealed that the development of the ovary is a product of an active signaling cascade, involving complex cell-cell interaction and cell fate determination. We have identified two novel molecules, WNT4 and follistatin, that play critical roles during early ovary development. Wnt4 and follistatin null mice had identical defects in embryonic ovaries including formation of a testis-specific vasculature and loss of germ cells. Furthermore, we found that follistatin is the direct downstream effector of WNT4 to regulate the vasculature and germ cell development. We therefore hypothesize that WNT4 and follistatin are constituents of a novel signaling cascade to inhibit testis-specific vasculature and to maintain the survival of female germ cells in ovary development. We propose three specific aims to: 1) dissect the intracellular signaling pathways of WNT4; 2) understand the regulation and functions of follistatin in ovary development; and 3) establish the functional relationship between formation of the testis specific vasculature and germ cell loss in follistatin null gonads. By combining transgenic and organ culture techniques, we expect to decipher the molecular and cellular pathways for the development of the ovary and at the same time, identify the critical components susceptible to genetic defects in these pathways.