Genetic analysis of male gonadal development

描述（申请人提供）：生殖细胞分布在性腺组织中，性腺组织介导生殖细胞分化为卵子和精子，从而繁殖大多数动物物种。在小鼠中，已经确定了一些在性腺早期发育中起作用的基因，提供了一个在性腺早期发育中起作用的分子因子框架。然而，这些因素如何协同作用介导性腺的体细胞和生殖细胞衍生部分的规范和分化仍然知之甚少。许多基因仍然缺失，起作用的分子机制仍然只是粗略地定义。此外，我们对脊椎动物生殖细胞的维持、存活和增殖，以及它们早期分化的机制知之甚少。例如，在体细胞和生殖细胞组织形成睾丸索和分化精管的过程中起作用的因素，或调节独特的精原细胞分裂程序和早期分化的机制几乎完全未知。尽管性别决定机制在斑马鱼和哺乳动物之间并不保守，但在初始性别决定决定的下游驱动性腺和生殖细胞发育的分子机制是保守的。斑马鱼提供了一个很好的遗传模型来进行正向遗传筛选，以识别在脊椎动物性腺发育中起作用的基因，这是一种对小鼠研究这一过程的反向遗传方法的补充。在这里，在斑马鱼中进行突变筛选的能力将被用于识别成年雄性性腺突变体。突变体将被表征，以确定缺陷的性质和生物过程中断。最后，突变将被映射到染色体位置，以促进种群的繁殖，并作为确定突变基因分子性质的起点。从这些筛选中，我们期望发现在雄性性腺组织的规范、形态发生和分化、生殖细胞的存活和增殖中起作用的新的重要基因，包括调节精原干细胞功能的基因和源自精原干细胞的细胞的早期分化过程。这些和未来对这些雄性不育突变体的研究可能会提供重要的见解，可能是环境毒物或基因导致男性低生育能力和睾丸癌的目标。

DESCRIPTION (provided by applicant): Germ cells populate somatic gonadal tissue, which mediates their differentiation into eggs and sperm to propagate most animal species. In the mouse a number of genes have been identified that function in early development of the gonad, providing a framework of molecular factors that act in early gonadal development. However, how these factors work together to mediate the specification and differentiation of the somatic and germ cell-derived portion of the gonad is still only very poorly understood. Many genes remain missing and the molecular mechanisms at work are still only loosely defined. Moreover, little is known in vertebrates about the maintenance, survival, and proliferation of the germ cells, or the mechanisms of their early differentiation. For example, the factors acting in the morphogenesis of the somatic and germ cell tissue into testis cords and differentiated seminiferous tubules, or the mechanisms regulating the distinctive spermatogonial cell division program and early differentiation are almost entirely unknown. Although sex determination mechanisms are not conserved between zebrafish and mammals, the molecular mechanisms driving gonadal and germ cell development downstream of the initial sex determination decision are conserved. The zebrafish provides an excellent genetic model to perform forward genetic screens to identify genes acting in vertebrate gonad development, a methodology complementary to the reverse genetic methods used in the mouse to study this process. Here, the ability to perform mutant screens in the zebrafish will be exploited to identify adult male gonadal mutants. The mutants will be characterized to determine the nature of the defect and the biological process disrupted. Lastly, the mutations will be mapped to chromosomal positions to facilitate propagating the stock and as a starting point to identify the molecular nature of the mutated gene. From these screens we expect to identify novel and important genes acting in the specification, morphogenesis, and differentiation of male gonadal tissue, the survival and proliferation of germ cells, including genes regulating spermatogonial stem cell function and the early differentiation process of cells derived from spermatogonial stem cells. These and future studies of this male sterile mutant collection will likely provide important insights, possibly targets of environmental toxicants or genes contributing to low fertility and testicular cancers in man.