Genetic analysis of male gonadal development

描述(申请者提供)：生殖细胞存在于体细胞性腺组织中，通过调节生殖细胞分化为卵子和精子来繁殖大多数动物物种。在小鼠中，已经确定了许多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的框架。然而，这些因素如何共同作用来调节性腺的体细胞和生殖细胞来源部分的指定和分化仍然知之甚少。许多基因仍然缺失，发挥作用的分子机制仍然只是一个粗略的定义。此外，脊椎动物对生殖细胞的维持、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向睾丸索和分化的生精小管的形态发生中起作用的因素，或者调控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。虽然斑马鱼和哺乳动物之间的性别决定机制不是保守的，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，这是一种补充小鼠用来研究这一过程的反向遗传方法的方法。在这里，在斑马鱼中进行突变筛选的能力将被用来识别成年雄性性腺突变。将对突变体进行特征分析，以确定缺陷的性质和扰乱的生物过程。最后，突变将被映射到染色体位置，以便于种群的繁殖，并作为鉴定突变基因的分子性质的起点。从这些筛选中，我们有望发现在男性性腺组织的规范、形态发生和分化、生殖细胞的存活和增殖方面发挥作用的新的和重要的基因，包括调控精原干细胞功能的基因和精原干细胞来源的细胞的早期分化过程。这些和未来对这种男性不育突变体集的研究可能会提供重要的见解，可能是环境毒物或导致男性低生育率和睾丸癌的基因的靶标。

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.