GCD MOUSE--MODEL FOR HUMAN AZOOSPERMIA

GCD小鼠——人类无精症模型

• 批准号: 6608245
• 负责人: COLIN Edward BISHOP
• 金额: $ 17.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608245
• 关键词: disease /disorder model; fertility; genetic regulation; genetically modified animals; laboratory mouse; male; male reproductive system disorder; model design /development; spermatogenesis

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.

生殖细胞发育是一个复杂的，严格有序的细胞分裂过程和分化的过程，从二倍体原始生殖细胞（PGC）隔离开始，并随着大量成熟的单倍倍形精子或卵母细胞的产生而结束。它是所有哺乳动物中生育能力的重要决定因素，在该物种的持久性中起着基本作用，维持其遗传多样性和驱动进化。最近，在识别在生殖细胞进展的后来减数分裂阶段中起作用的基因方面取得了长足的进步。但是，对于PGC开发最早阶段所涉及的途径知之甚少。发展。实际上，小鼠中只有四个基因对PGC（MGF，KIT，TER，GCD）具有已知的特定作用。每种突变导致PGC缺乏和生育问题。除GCD外，这些突变是多效性的，使对特定生殖细胞成分的分析更加困难。本提案旨在通过确定与PGC迁移和扩散有关的特定基因来填补这一空白。非透明生殖细胞缺乏（GCD）小鼠突变体将用作模型系统。对该突变体的分析清楚地表明，单个基因座的破坏可以大大减少胚胎性腺中的PGC，从而导致雄性和女性不育症。严重的寡素体的男性表型迅速是Azoospermia，只有几个功能性小管，与在不育的人类男性中仅观察到的只有人类Sertoli细胞综合征（SCO）非常相似。该项目的具体目的旨在使用位置克隆和基因靶向确定GCD表型的基因。它的结构，时空表达模式以及通过通过转基因重新引入GCD/GCD小鼠来研究的可能。 GCD的克隆代表了一个独特的机会，可以获得对原始细菌的基本生物学的新见解以及人类不孕症的棘手问题。它将使我们能够检查GCD基因本身或控制中的途径中的错误可能性是人类中大部分此类案例的可能性。