Biology of the ErbB Gene Family in Spermatogonial Development

Ut Southwestern Medical Center, Dallas TX

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Abstract

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