About 2.5 million couples in the US are infertile, representing a major health and social problem. However, our understanding of the underlying genetics of reproduction-gametogenesis in particular- is relative poor. One way to address this issue is to derive mammalian models of reproductive failure, and identify the genes that play roles in the process. This Program Project will use the laboratory mouse, in a forward genetics mutagenesis strategy, to generate the largest collection of mammalian gametogenesis mutants ever established. The value of this resource to the research community will depend largely upon the degree to which the mutations are characterized, the ease with which the mutants can be maintained, and sufficient genetic information to relate mutant phenotypes to particular genes or chromosomal regions. The goals of this project are to genetically map 100 new infertility mutations representing a range of steps in gametogenesis, including stem cell proliferation, meiosis, somatic cell-germ interaction, and post-meiotic development. The linkage of a mutation to molecular markers will facilitate stock maintenance and distribution to colleagues around the world. In addition, a subset of mutations affecting certain aspects of spermatogenesis and oogenesis, selected in consultation with the other Principle Investigators of the Program Project, will be genetically mapped to high resolution as a prelude to positional cloning. Finally, up to ten mutations that primarily affect the regulation of meiosis, recombination, and meiotic chromosome behavior will be positionally cloned to understand the function of the underlying gene products.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD042137-01
Application #
6606592
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2002-09-01
Project End
2007-06-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Fujiwara, Yasuhiro; Matsumoto, Hirokazu; Akiyama, Kouyou et al. (2015) An ENU-induced mutation in the mouse Rnf212 gene is associated with male meiotic failure and infertility. Reproduction 149:67-74
Sun, Fengyun; Fujiwara, Yasuhiro; Reinholdt, Laura G et al. (2015) Nuclear localization of PRDM9 and its role in meiotic chromatin modifications and homologous synapsis. Chromosoma 124:397-415
Pattabiraman, Shrivatsav; Baumann, Claudia; Guisado, Daniela et al. (2015) Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. J Cell Biol 208:53-69
Harris, Tanya P; Schimenti, Kerry J; Munroe, Robert J et al. (2014) IQ motif-containing G (Iqcg) is required for mouse spermiogenesis. G3 (Bethesda) 4:367-72
Bentson, L F; Agbor, V A; Agbor, L N et al. (2013) New point mutation in Golga3 causes multiple defects in spermatogenesis. Andrology 1:440-50
Luo, Mengcheng; Yang, Fang; Leu, N Adrian et al. (2013) MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nat Commun 4:2788
Li, Xin Zhiguo; Roy, Christian K; Dong, Xianjun et al. (2013) An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Mol Cell 50:67-81
Liu, Ye; Zaun, Hans C; Orlowski, John et al. (2013) CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. J Neurosci 33:12656-69
Fujiwara, Yasuhiro; Ogonuki, Narumi; Inoue, Kimiko et al. (2013) t-SNARE Syntaxin2 (STX2) is implicated in intracellular transport of sulfoglycolipids during meiotic prophase in mouse spermatogenesis. Biol Reprod 88:141

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