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.
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