Unveil a Novel Pathway in Mammalian Ovary Development

揭示哺乳动物卵巢发育的新途径

• 批准号: 7326853
• 负责人: Humphrey Hung-Chang Yao
• 金额: $ 31.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326853
• 关键词: Activins; Adult; Cell Communication; Cell Survival; Cells; Code; Color; Complex; Defect; Development; Embryo; Embryonic Development; Female; Follistatin; Germ Cells; Germ Lines; Goals; Gonadal structure; Individual; Infertility; Knockout Mice; Lead; Maps; Molecular; Mutate; Mutation; Nature; Neoplasms; Oranges; Organ Culture Techniques; Ovary; Pathway interactions; Play; Primordium; Process; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Testis; Time; Transgenic Organisms; WNT4 gene; design; human WNT4 protein; novel; reproductive; sertoli cell

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.

描述（由申请人提供）：胚胎性腺的发展是确定成年人生殖功能的第一步。当性腺发育早期出现缺陷时，就会出现性歧义，不育或肿瘤。该提案的主要目标是了解性腺发展的基本过程，尤其是关于卵巢的发展。哺乳动物卵巢的发展被认为是默认途径，仅在没有定向的睾丸途径的情况下就产生。但是，我们最近的发现表明，卵巢的发展是活动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的测定。我们已经确定了两个新型分子Wnt4和Follistatin，它们在早期卵巢发育过程中起着关键作用。 Wnt4和Follistatin null小鼠在胚胎卵巢中具有相同的缺陷，包括形成睾丸特异性脉管系统和生殖细胞的丧失。此外，我们发现Follistatin是Wnt4的直接下游效应子，用于调节脉管系统和生殖细胞发育。因此，我们假设Wnt4和Follistatin是一种新型信号级联的组成部分，可抑制睾丸特异性脉管系统，并维持雌性生殖细胞在卵巢发育中的存活。我们提出了三个特定的目的：1）剖析Wnt4的细胞内信号通路； 2）了解卵泡素在卵巢发育中的调节和功能； 3）建立睾丸特异性脉管系统的形成与卵泡蛋白无性腺的生殖细胞损失之间的功能关系。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，同时确定易受这些途径中遗传缺陷的关键成分。