THE DAZ GENES AND EARLY GERM CELL DEVELOPMENT

近5%的男性在精子产生方面有缺陷，但在其他方面都很健康。我们之前的工作导致确定了男性不孕症的一个常见遗传原因，即Y染色体DAZ（在无精子症中缺失）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。一些证据表明，该基因家族是生殖细胞分配或增殖和维持早期生殖细胞群体所必需的。首先，蛋白质表达模式表明DAZ和常染色体同源物DAZL在所有生殖谱系的后代中都具有早期功能。其次，尽管DAZ基因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基因缺失的男性在精子产生方面存在早衰缺陷，而不是精子发生方面的缺陷。第三，小鼠DAZ基因同源性的破坏导致两性不育和生殖细胞的耗尽，早在减数分裂之前。最后，DAZ的爪蟾同源物X-Dazl在胚质中表达，胚质是胚胎发育的一个区域，在这种生物中产生生殖谱系。本研究将使用生化、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体分配、维持和增殖的机制。具体来说，我们在未来五年的目标是：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)鉴定和表征其他基因，这些基因具有与DAZ基因家族成员相同的独特表达模式，使用来自不同生精阻滞表型的男性睾丸活检组织。

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.