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.
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.
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