GCD MOUSE--MODEL FOR HUMAN AZOOSPERMIA

生殖细胞发育是一个复杂的、严格有序的细胞分裂和分化过程，从二倍体原始生殖细胞（PGCs）从体细胞谱系中分离开始，以大量成熟的单倍体精子或卵母细胞的产生结束。它是所有哺乳动物生育力的重要决定因素，在物种的延续中发挥着重要作用，保持其遗传多样性并推动进化。最近，在鉴定在生殖细胞发育的后期减数分裂阶段起作用的基因方面取得了相当大的进展。然而，很少有人知道参与PGC发展的最早阶段的途径。发展事实上，小鼠中只有四个基因对PGCs有已知的特异性作用（MGF，Kit，Ter，gcd）。每种基因的突变都会导致PGC缺乏和生育问题。除了gcd，这些突变是多效性的，使得分析特定的生殖细胞成分更加困难。目前的建议是为了填补这一空白，在我们的知识，通过确定特定的基因参与的迁移和增殖的PGCs。非多效性生殖细胞缺陷（gcd）小鼠突变体将用作模型系统。对这种突变体的分析清楚地表明，在单个位点的破坏可以大大减少胚胎性腺中的PGCs，从而引起男性和女性不育。严重少精子症的男性表型，随后是只有少数功能性小管的无精子症，与在不育男性中观察到的人类支持细胞综合征（SCOS）非常相似。本计画的特定目标是利用定位克隆与基因定位技术来鉴定gcd表型的基因。该基因的结构、时空表达模式以及通过转基因将其重新导入gcd/gcd小鼠的可能性。gcd的克隆为我们提供了一个独特的机会，使我们能够对原始生殖细胞系的基础生物学和人类不育这一棘手问题有新的认识。它将使我们能够检查GCD基因本身或对照中的通路中的错误的可能性，这些错误是人类中此类病例的显著百分比的基础。

Germ cell development is a complex, strictly ordered process of cell division and differentiation starting with the segregation of diploid primordial germ cells (PGCs) from the somatic lineage and finishing with the production of large numbers of mature haploid spermatozoa or oocytes. It is an essential determinant of fertility in all mammals, playing a fundamental role in the perpetuation of the species,, maintaining its genetic diversity and driving evolution. Recently, considerable progress has been made in identifying genes that play a role in the later meiotic stages of germ cell progression. However, very little is known about the pathways involved in the very earliest stages of PGC development. development. In fact, only four genes in the mouse have known, specific effects on PGCs (MGF, Kit, Ter, gcd). Mutations in each cause PGC deficiency and fertility problems. With the exception of gcd, these mutations are pleiotropic making an analysis of the specific germ cell component more difficult. The present proposal is designed to fill this gap in our knowledge, by identifying specific genes involved in the migration and proliferation of PGCs. The non-pleiotropic germ cell deficient (gcd) mouse mutant will be used as a model system. Analysis of this mutant clearly shows that disruption at a single locus, can drastically reduce the PGCs in the embryonic gonad, giving rise to male and female infertility. The male phenotype of a severe oligospermia quickly followed by azoospermia with only a few functional tubules, is very similar to the human Sertoli Cell Only syndrome (SCOS) seen in infertile human males. The specific aims of this project are designed to identify the gene underlying the gcd phenotyping using positional cloning and gene targeting. Its structure, spatio-temporal expression pattern and possible of studied by reintroducing the gene into gcd/gcd mice via transgenesis. That the cloning of gcd represents a unique opportunity to gain new insights into the fundamental biology of primordial germ lines and the intractable problem of infertility in humans. It will allow us to examine the possibility that errors in the GCD gene itself, or in a pathway which in controls, underlie a significant percentage of such cases in human.