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Project Description:

The overarching goal of the proposed research is to identify genes and unravel novel mechanisms responsible for sperm differentiation. This will further our understanding of normal development and aid in the treatment of human infertility. Male infertility accounts for about half of all infertility cases and a large percentage of these cases are proposed to be genetic in nature. Genetic mouse models of infertility will be used to accomplish this goal. Because the genomes of humans and mice are so similar, genes and pathways important for the regulation of spermatogenesis are probably common to the two species. Mice with the repro27 chemically-induced mutation display male-specific infertility. Spermatogenesis in C3Fe;B6-repro27 mutant mice is disrupted in late meiosis leading to cell death. Abnormal spermiogenesis is evident in the surviving germ cells. Overt defects appear to be restricted to the testes and females are reproductively normal. In repro27 mice, we identified a point mutation in the golgin subfamily A member 3 (Golga3) gene that inserts a stop codon into exon 18. Protein expression analysis suggests that GOLGA3 protein is degraded in repro27 mutant mice rather than truncated. As the name implies, GOLGA3 (i.e. golgin-160, MEA2) is a Golgi complex-associated protein that has been implicated in protein trafficking of a certain proteins, apoptosis, and spermatogenesis. GOLGA3 is highly expressed in the testis but its expression is not restricted to this tissue. The precise function of GOLGA3 in the testes is not known. The objective of this proposal is to understand the involvement of GOLGA3 in spermatogenesis by utilizing repro27 mutant mice known to carry a mutation in this gene. The central hypothesis is that repro27 mutant mice exhibit multiple spermatogenesis defects resulting from disrupted GOLGA3-dependent pathways. repro27 mice will be used to 1) conduct spermatogonial stem cell transplant experiments to determine if GOLGA3 function is germ cell specific; and 2) study the role of GOLGA3 in the testis at transcriptional and post-translational levels. The underlying rationale for studying GOLGA3 specifically in the testis, is that genes and pathways identified in the mouse may be homologous in humans, thus providing new clues and treatment options for human male infertility.