This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overarching goal of this research is to identify genes and unravel novel mechanisms of gene expression responsible for male fertility. Two genetic mouse models, C3Fe;B6-repro27 (repro27) and C3Fe;B6-repro29 (repro29) are being used to accomplish this goal. Both strains exhibit defects in sperm development leading to gender-specific infertility. Mice with two copies of the repro27 mutation exhibit significant germ cell death during meiosis and defects in differentiation including sperm head and tail formation. We have identified a point mutation in the golgin subfamily A member 3 (Golga3) gene that inserts a premature stop codon into the transcript. Golga3 encodes a Golgi apparatus-associated protein involved in protein trafficking, apoptosis signaling, and spermatogenesis. The role of GOLGA3 in spermatogenesis is unknown. We are investigating mechanisms of GOLGA3 action in spermatogenesis by utilizing repro27 mutant mice. Defects in repro29 mice are evident in late spermatogenesis causing head and tail abnormalities that prevent fertilization of the egg. We are using meiotic recombinant mapping strategies to identify the gene responsible for the repro29 phenotype. We have narrowed the candidate gene region from 30 Mb to 1.57 Mb on Chr 5;this region contains 40 known genes currently being evaluated for differential sequence and gene expression patterns. Experiments using repro27 and repro29 mice will ultimately allow the identification of new genes and pathways that may be homologous in humans providing new clues and treatment options for human male infertility.
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