THE DAZ GENES AND EARLY GERM CELL DEVELOPMENT

DAZ 基因和早期生殖细胞发育

• 批准号: 6603242
• 负责人: Renee A Reijo Pera
• 金额: $ 19.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603242
• 关键词: RNA; RNA binding protein; chromosome deletion; clinical research; developmental genetics; embryogenesis; fertility; gene deletion mutation; gene expression; genetic mapping; germ cells; human genetic material tag; human subject; immunocytochemistry; immunoprecipitation; karyotype; male; nucleic acid sequence; phenotype; protein protein interaction; sex chromosomes; site directed mutagenesis; spermatogenesis; testis; yeast two hybrid system

Nearly five percent of men have defects in sperm production but are otherwise healthy. Our previous work led to identification of a common genetic cause of infertility in men, de novo deletions of the DAZ (Deleted in AZoospermia) region of the Y chromosome. Within this region, we identified a cluster of nearly-identical DAZ genes. Several lines of evidence suggest that this gene family is required for germ cell allocation or proliferation and maintenance of early germ cell populations. First, the protein expression pattern suggests an early function for DAZ and an autosomal homolog, DAZL, in all descendants of the germ lineage. Second, although men with deletions of the DAZ gene cluster produce very few sperm, those they do make are morphologically and physiologically normal which suggests DAZ-deleted men have a premeiotic defect in sperm production rather than a defect in spermiogenesis. Third, disruption of the DAZ gene homolog in mice causes infertility in both sexes and depletion of germ cells prenatally, well before meiosis. Finally, the Xenopus homolog of DAZ, X-Dazl, is expressed in the germ plasm, a region of the developing embryo that gives rise to the germ lineage in this organism. This investigation will use biochemical, genetic and molecular biological strategies to elucidate the mechanism by which the DAZ gene family insures that allocation or maintenance and proliferation of early germ cell populations occurs. Specifically, our aims over the next five years are to: 1) Identify and characterize the genes that encode protein(s) that interact with DAZ-protein, 2) identify and characterize the genes that encode RNA substrate(s) that interact with DAZ protein, and 3) identify and characterize other genes, with the same distinctive pattern of expression as exhibited by members of the DAZ gene family, using testicular biopsy tissues from men with different spermatogenic arrest phenotypes.

近百分之五的男性在精子生成方面存在缺陷，但在其他方面都很健康。 我们之前的工作确定了男性不育的常见遗传原因，即 Y 染色体 DAZ（AZoospermia 缺失）区域的从头缺失。 在这个区域内，我们发现了一组几乎相同的 DAZ 基因。 多项证据表明，该基因家族是生殖细胞分配或增殖以及早期生殖细胞群维持所必需的。首先，蛋白质表达模式表明 DAZ 和常染色体同源物 DAZL 在胚系的所有后代中都具有早期功能。 其次，虽然DAZ基因簇缺失的男性产生的精子很少，但他们产生的精子在形态和生理上都是正常的，这表明DAZ缺失的男性在精子产生方面存在减数分裂前缺陷，而不是在精子发生方面存在缺陷。 第三，小鼠中 DAZ 基因同源物的破坏会导致两性不育，并在产前（减数分裂之前）导致生殖细胞耗尽。最后，DAZ 的爪蟾同源物 X-Dazl 在种质中表达，种质是发育中胚胎的一个区域，在该生物体中产生种系。 这项研究将使用生化、遗传和分子生​​物学策略来阐明 DAZ 基因家族确保早期生殖细胞群的分配或维持和增殖发生的机制。 具体来说，我们未来五年的目标是：1) 鉴定和表征编码与 DAZ 蛋白相互作用的蛋白质的基因，2) 鉴定和表征编码与 DAZ 蛋白相互作用的 RNA 底物的基因，以及 3) 使用来自具有不同生精能力的男性的睾丸活检组织，鉴定和表征具有与 DAZ 基因家族成员所表现出的相同独特表达模式的其他基因。 逮捕表型。