Biology of the ErbB Gene Family in Spermatogonial Development

该项目将通过定义分子机制， 指导睾丸内的干细胞发育成精子，最终使卵子受精。 睾丸干细胞在发育过程中不断发育成精子的生物学过程 成年雄性的生殖期称为精子发生。目前，我们对 关于精子发生是如何在干细胞水平上被我们体内的激素调节的。 因此，本申请的长期目标将是研究睾丸内分泌学 成红细胞瘤病毒B（Erb B）基因家族的激素受体。这些目标是基于 新的初步研究提供了明确的证据，表明组成ErbB家族的基因是 密切参与调节精原细胞发育。我们发现了一种独特的细胞 睾丸中的ErbB型差异表达由ErbB中的四个基因编码的受体亚基。 家族（即ErbB1、ErbB2、ErbB3和ErbB4）。因此，刺激细胞的激素 ErbB的作用，称为Neuregulins，也独特地由不同的睾丸细胞类型表达。 作为本次赠款申请的近期目标，根据美国复苏和再投资计划， 2009年法案（ARRA），我们提出了两个具体目标，重点是了解 精子发生过程中表达ErbB3基因的生殖细胞的发育命运。这是 因为我们最近发现ErbB3在精原干细胞特异性表达， 细胞在一个关键的时间，当他们被认为是精神上指示启动 精子发生在具体目标1中，我们将进行关键的组织学和细胞生物学研究 这将有助于构建发育命运图，以显示精原细胞 干细胞表达ErbB 3。一旦组装完成，这张命运图将在细胞水平上说明 精原干细胞启动啮齿动物精子发生的过程。作为另一把钥匙 在这一过程中，特定目标2将建立一种新的遗传方法，系统地标记 啮齿动物精原干细胞与重要的荧光标记作为一种方法来跟踪他们的 行为之前，期间和之后，他们进入精子发生。因此，每个目标都侧重于 进一步了解ErbB3的功能影响，以触发一个新的子集， 精原干细胞开始通过精子发生的最早步骤

This project will significantly impact biology and medicine by defining molecular mechanisms that instruct stem cells within the testes to develop into sperm for the ultimate fertilization of eggs. The biological process by which stem cells in the testis continuously develop into sperm during the reproductive life of the adult male is termed Spermatogenesis. Currently, very little is known about how spermatogenesis is regulated at the level of the stem cell by hormones in our body. Therefore, the long term goals of this application will be to investigate the testicular endocrinology of the Erythoblastoma Virus B (ErbB) gene family of hormone receptors. These goals are based on new preliminary studies providing clear evidence that genes comprising the ErbB family are intimately involved in regulating spermatogonial development. We have found that distinct cell types in the testis differentially express receptor subunits encoded by four genes in the ErbB family (i.e. ErbB1, ErbB2, ErbB3 and ErbB4). Accordingly, hormones that stimulate the cellular effects of ErbBs, termed Neuregulins, are also uniquely expressed by different testis cell types. As the immediate goals of this grant application, under the American Recovery & Reinvestment Act of 2009 (ARRA), we propose two Specific Aims that focus on understanding the developmental fate of germ cells expressing the ErbB3 gene during spermatogenesis. This is because we have recently discovered ErbB3 to be specifically expressed by spermatogonial stem cells at a pivotal time when they are thought to be hormonally instructed to initiate spermatogenesis. In Specific Aim 1, we will perform key histological and cellular biology studies that will be instrumental in constructing a developmental fate map to show when spermatogonial stem cells express ErbB3. Once assembled, this fate map will illustrate at a cellular level how spermatogonial stem cells initiate the process of spermatogenesis in rodents. As another key step in this process, Specific Aim 2 will establish a novel genetic approach to systematically label rodent spermatogonial stem cells with vital fluorescent markers as a method to track their behavior before, during and after their entry into spermatogenesis. Thus, each aim focuses on progressing toward understanding the functional impact of ErbB3 to trigger a novel sub-set of spermatogonial stem cells to commence through the earliest steps in spermatogenesis