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 调节精原干细胞发育的基因。每一个具体目标都集中在定义 一个存活、增殖和分化家族的结构、功能和睾丸内分泌 因子，称为neuregulins。神经调节蛋白包含用于跨膜调节的配体的大家族。 成纤维细胞瘤病毒B（Erb B）酪氨酸激酶家族中的受体。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一起表达， 神经调节蛋白样因子是培养物中排列的精原细胞形成所必需的。的 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的目标是确定神经调节蛋白和ErbB的结构 家族成员在培养的未分化精原细胞中表达。配体-受体对 然后将用于确定神经调节蛋白调节精原细胞的机制。 文化的发展。具体目标2将侧重于定义空间和时间表达， 一种神经调节蛋白受体，称为ErbB 3，在大鼠睾丸中。初步研究表明， ErbB 3高度局限于大鼠睾丸内的A型单个精原细胞。因为A型单身 精原细胞被认为是干精原细胞，并且因为用于 这些细胞还没有被定义，ErbB 3表达精原细胞将被测试它们的能力， 在嵌合啮齿动物睾丸中作为精原干细胞发挥功能，如特异性目的3。拟议 项目应该对人类健康产生积极影响;阐明分子机制， 调节精原细胞发育可能会导致治疗和治愈男性不育症， 为避孕药具的发展提供新的目标，协助保护濒危物种， 提供了替代方法来生产在医学上有价值的转基因动物，并可能允许 用于对男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.