Molecular Mechanisms of Spermatogonial Development

该项目将通过更好地定义分子机制，对生物学和医学产生重大影响 来调控精原干细胞的发育。每个具体目标都集中在定义 一个生存、增殖和分化家族的结构、功能和睾丸内分泌学 因子，称为中性调节蛋白。神经调节蛋白由跨膜配体大家族组成 红母细胞瘤病毒B(ErbB)家族酪氨酸激酶的受体。初步研究表明 神经调节蛋白及其受体在未分化的精原细胞上共同表达，以及 在培养中形成排列整齐的精原细胞需要神经调节素样因子。这个 拟议的研究是基于这些发现，并将代表一个新的调查领域 生殖生物学。具体目标1的目标是定义NeuRegin和ErbB的结构 家族成员在培养中以未分化的精原细胞表达。配基-受体对 鉴定后将用于确定神经调节素调节精原细胞的机制 文化方面的发展。具体目标2将侧重于定义空间和时间表达 大鼠睾丸中的一种神经调节蛋白受体，称为ErbB3。初步研究表明， ErbB3高度局限于大鼠睾丸内的A型单个精原细胞。因为A型-单人 精原细胞被认为是干细胞精原细胞，因为特定的分子标志物 这些细胞还没有定义，表达ErbB3的精原细胞将被测试它们的能力 在嵌合的啮齿动物睾丸中作为精原干细胞的功能，作为特定的目标3.建议的 项目应该对人类健康产生积极影响；阐明分子机制 调节精原发育很可能导致治疗和治愈男性不育， 为避孕措施的开发提供新的目标，协助保护濒危物种， 提供替代方法来生产有医学价值的转基因动物，并有可能允许 用于对雄性生殖系中有害的遗传缺陷进行选择。

This project will significantly impact biology and medicine by better defining molecular mechanisms that regulate spermatogonial stem cell development. Each specific aim is centered on defining the structure, function and testicular endocrinology of a family of survival, proliferation and differentiation factors, termed neuregulins. Neuregulins comprise a large family of ligands for transmembrane receptors in the erythoblastoma virus B (ErbB) family of tyrosine kinases. Preliminary studies show that neuregulins and their receptors are expressed together on undifferentiated spermatogonia, and that neuregulin-like factors are required for formation of aligned spermatogonia in culture. The proposed studies are based on these findings and will represent a new area of investigation in reproductive biology. The goal of Specific Aim 1 is to define the structures of neuregulin and ErbB family members expressed by undifferentiated spermatogonia in culture. Ligand-receptor pairs identified will then be used to determine mechanisms by which neuregulins regulate spermatogonial development in culture. Specific Aim 2 will focus on defining the spatial and temporal expression of one neuregulin receptor, termed ErbB3, in the rat testes. Preliminary studies show that expression of ErbB3 is highly restricted to type A-single spermatogonia within rat testes. Because type A-single spermatogonia are considered stem spermatogonia, and because specific molecular markers for these cells have yet to be defined, ErbB3-expressing spermatogonia will be tested for their ability to function as spermatogonial stem cells in chimeric rodent testes, as Specific Aim 3. The proposed project should have a positive impact on human health; elucidating molecular mechanisms that regulate spermatogonial development may well lead to treatments and cures for male infertility, provide new targets for contraceptive development, assist in the preservation of endangered species, afford alternative methods to produce transgenic animals valuable in medicine, and potentially allow for selection against harmful genetic defects in the male germline.