This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Genetic mouse models provide valuable in vivo tools to study the regulation of mammalian reproduction. Approximately 99% of the roughly 40,000 genes within the two genomes are conserved between mice and humans and thus, genes important for regulation of spermatogenesis are likely conserved between the two species. C3Fe;B6-repro27 and C3Fe:B6-repro29 are genetic mouse models produced using the chemical mutagen ethylnitrosourea. The mutations are recessively inherited and male specific. Male repro27 homozygotes display defects during the first wave of meiosis leading to significant germ cell loss. Surviving germs cells show defects in spermiogenesis characterized by the delayed formation of elongated spermatids wtih abnormally shaped sperm heads and no tails. Mutant testes are very small, epididymal sperm concentration is very low with low motility and no success with in vitro fertilization. C3Fe;B6-repro29 mice share several of the male-specific spermatogenic defects found in repro27 mice. Our data suggests that the repro27 phenotype is caused by a point mutation in the Golga3 gene located on Chr5. Golga3 encodes a golgi autoantigen, a member of the golgin protein family. The GOLGA3 protein is important for the redistribution of the Golgi apparatus during mitosis, plays a role in apoptosis, and is required sperm development. The repro29 mutation maps to Chr 5; sperm have defective heads and tails, and very low IVF success. However, testes weights are normal and the defect appears to be post-meiotic. Research will focus on the following specific aims 1. morphological and histological characterize spermatogenesis in C3Fe;B6-repro29; 2. genetically map the repro29 mutation using meiotic recombinants to narrow the candidate gene region; and 3. DNA sequence candidate genes to identify the genetic defect in C3Fe:B6-repro29 mice. The identification of genes and elucidation of the pathways required for normal germ cell development will help unravel the causes of human infertility.
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