For the past five years, the ReproGenomics Program at The Jackson Laboratory has produced novel mutant models of infertility as a resource for the community of reproductive biologists. The mutations produced and mapped by this program in this relatively short period of time represent ~10% of the total infertility mutations documented throughout the history of mouse research. These efforts have generated a unique resource of models for the study of gonadogenesis, gametogenesis, meiosis, and gamete function. The objectives of this continuation application are to 1) utilize ReproGenomics mutant models, as well as other genetic models, for investigation of several themes underlying gametogenesis that were generated and characterized in this program, and 2) expand the depth and breadth of the resource by generating additional autosomal mutations, plus X-linked mutations derived using new technology developed in the Program. The focus of Project I is on a gene family expressing bromodomains and involved in chromatin remodeling and/or transcriptional control during gametogenesis;the focus of Project II is on critical aspects of early meiotic prophase in spermatocytes;and the focus of Project III is on the oocyte-to-embryo transition. Core A will continue successful production of autosomal ENU-induced infertility phenotypes as well as a novel resource of X-linked infertility mutations, and Core B will conduct fine mapping and positional cloning of selected mutations. Production of mutant models by a method selecting mutations on the X chromosome will add depth to the resource, and these mutations will be of further scientific importance because the X chromosome has never been targeted in forward ENU mutagenesis screens. The program will continue to encourage other researchers in the community of reproductive biologists to study the mutations already and yet to be produced. This Program Project 1) provides community resources, 2) is a framework for totally unbiased discovery research that will enable new directions by other investigators, and 3) addresses important questions about gametogenesis using novel mutant models with relevant phenotypes that were produced in the Program Project.

Public Health Relevance

to Public Health: This Program Project will help establish the etiology for what are now poorly understood and untreatable cases of human infertility. By defining mechanisms of gametogenesis, the program will contribute to still rudimentary knowledge of what constitutes a good gamete, and thereby help establish standards guiding assisted reproductive technologies. Finally, by resolving mechanisms for mutations whose sole phenotype is infertility, the program will contribute to the basic knowledge foundation that underpins management of both fertility and infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD042137-10
Application #
8325961
Study Section
Special Emphasis Panel (ZHD1-DSR-L (EJ))
Program Officer
Taymans, Susan
Project Start
2002-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$967,431
Indirect Cost
$306,171
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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
Schimenti, Kerry J; Feuer, Sky K; Griffin, Laurie B et al. (2013) AKAP9 is essential for spermatogenesis and sertoli cell maturation in mice. Genetics 194:447-57
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
Gómez, Rocío; Jordan, Philip W; Viera, Alberto et al. (2013) Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis suggests functions in distinct chromosome processes. J Cell Sci 126:4239-52
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
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

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