Genetic analysis of male gonadal development

描述（由申请方提供）：生殖细胞填充体细胞性腺组织，介导其分化为卵子和精子，以繁殖大多数动物物种。在小鼠中，已经鉴定出许多在性腺早期发育中起作用的基因，提供了在性腺早期发育中起作用的分子因子的框架。然而，这些因素如何共同作用，以介导的规范和生殖腺的体细胞和生殖细胞衍生的部分分化仍然是非常少的了解。许多基因仍然缺失，工作的分子机制仍然只是松散的定义。此外，对脊椎动物生殖细胞的维持、存活和增殖，或其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的曲细精管的形态发生中起作用的因素，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。虽然性别决定机制在斑马鱼和哺乳动物之间并不保守，但在最初的性别决定决定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，以确定在脊椎动物性腺发育中起作用的基因，这是一种与小鼠中用于研究这一过程的反向遗传方法互补的方法。在这里，在斑马鱼中进行突变体筛选的能力将被用来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被破坏的生物过程。最后，突变将被定位到染色体位置，以促进繁殖的股票，并作为一个起点，以确定突变基因的分子性质。从这些屏幕上，我们希望确定新的和重要的基因作用于规范，形态发生和分化的男性性腺组织，生殖细胞的生存和增殖，包括基因调节精原干细胞的功能和早期分化过程中的细胞来自精原干细胞。这些和未来对这种雄性不育突变体的研究可能会提供重要的见解，可能是环境毒物或导致人类低生育力和睾丸癌的基因的目标。 公共卫生相关性：这里发现的基因和研究的过程可能会提供重要的见解，可能是环境毒物的目标，或者是导致人类生育力低下和睾丸癌的基因。我们发现的男性生育缺陷可能会出现在特定的人类生殖障碍和不育症中。在斑马鱼中鉴定出导致这些缺陷的基因将提供导致人类缺陷的候选基因，这最终可能导致基因检测或治疗干预。

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. PUBLIC HEALTH RELEVANCE: The genes discovered and processes studied here will likely provide important insights, possibly targets of environmental toxicants, or genes contributing to low fertility and testicular cancers in man. The male fertility defects we identify may be seen in specific human reproductive disorders and sterilities. Identification of the genes responsible for these defects in the zebrafish will provide candidate genes responsible for the human defects, which could ultimately lead to genetic testing or therapeutic intervention.