Opposing Pathways in Mammalian Sex Determination

哺乳动物性别决定的相反途径

基本信息

批准号：
7863893
负责人：
Blanche Capel
金额：
$ 1.04万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The gonad forms as a bipotential primordium that can develop into a testis or an ovary. As it develops it reveals the remarkable plasticity of cell fate and the finely balanced signaling mechanisms that compete to establish the male or female pathway. A Y-linked gene, Sry, controls male sex determination by initiating both Sertoli cell fate determination and the morphological organization of testis cords. In the past decade, much has been learned about downstream pathways that regulate testis morphogenesis. However, little is known about how Sry initiates this process. Available data suggests that transient expression of Sry controls a cell fate decision in Sertoli cell precursors that leads to the stable expression of Sox9 throughout the Sertoli lineage. Coincident with this process, Sertoli precursors begin to aggregate around germ cells, epithelialize, and undergo a process of de novo cord formation. Our hypothesis is that the fate determination step and the mesenchymal to epithelial transition of Sertoli precursor cells are molecularly linked through stabilized expression of SOX9. Investigation of this hypothesis will be the broad direction of our work during this funding period with emphasis on four main areas of focus. (1) Based on our previous work, we will use a lineage tracing approach to investigate how Sertoli precursors arise and activate Sox9 expression. (2) We have recently found molecular evidence for the competition of antagonistic pathways during Sertoli fate determination. Using mouse mutants, we will investigate how opposing signaling pathways and transcriptional networks result in the activation of the male pathway and the repression of the female pathway. (3) We plan to determine how the polycomb group chromatin remodeling protein, M33, is involved in the establishment of ovarian or testis developmental pathways using chromatin immunoprecipitation assays and M33 mutant mice. (4) We will investigate how testis cords form, and whether cord formation is linked to Sertoli cell differentiation through an interaction between SOX9 and MAP genes using live imaging, chimeric mice, markers of cell polarity and cell adhesion, and mice carrying mutations in cMaf and Mafb, members of a family shown to be critical for gonadogenesis in Drosophila, and known to interact with SOX9 during chondrogenesis in mammals.

描述（由申请人提供）：性腺形成是可以发展成睾丸或卵巢的双势基础的。随着它的发展，它揭示了细胞命运的显着可塑性以及竞争建立男性或女性途径的精致平衡信号传导机制。 Y连锁的基因SRY通过启动Sertoli细胞命运的确定和睾丸线的形态组织来控制男性的性别确定。在过去的十年中，关于调节睾丸形态发生的下游途径已经了解了很多。但是，关于Sry如何启动这一过程知之甚少。可用的数据表明，SRY的瞬态表达控制着Sertoli细胞前体中的细胞命运决策，从而导致整个Sertoli谱系中SOX9的稳定表达。与这一过程一致，Sertoli前体开始在生殖细胞周围聚集，上皮化并经历从头形成的过程。我们的假设是，命运的确定步骤和Sertoli前体细胞的间质向上皮过渡通过SOX9的稳定表达通过分子联系。对这一假设的调查将是我们在这项资金期间工作的广泛方向，重点是四个主要重点领域。（1）基于我们以前的工作，我们将使用一种谱系追踪方法来研究Sertoli前体如何出现并激活SOX9的表达。（2）我们最近发现了Sertoli命运确定期间拮抗途径竞争的分子证据。使用小鼠突变体，我们将研究相反的信号通路和转录网络如何导致男性途径的激活和女性途径的抑制。（3）我们计划确定Polycomb染色质重塑蛋白M33如何使用染色质免疫沉淀测定法和M33突变小鼠参与卵巢或睾丸发育途径。（4）我们将研究睾丸线的形成方式，以及是否使用活成像，嵌合小鼠，细胞极性和细胞粘附的标志物以及在CMAF和MAFB中携带突变的小鼠在CMAF和MAFB中与SOX相互作用至关重要的SOX在Drosogeny中相互作用至关重要的小鼠通过SOX9与MAP基因之间的相互作用与Sertoli细胞分化有关。哺乳动物。