This Program Project will develop an unprecedented resource for mammalian reproductive biologists: mutant mouse models of infertility. The approach will be to induce mutations in mice that cause infertility, map them, and provide a morphological, functional, and molecular characterization of phenotype. The proposed strategy will reap a spectrum of mutations affecting virtually all aspects of reproductive function, including neuroendocrine and behavioral aspects, but especially gonadogenesis, gametogenesis, meiosis, ovulation, fertilization and early embryo development. While some of these are of interest to the PIs of this Program, an important goal of this Program is to provide resources to the scientific community of reproductive biologists. The Mutagenesis and Phenotypic Screening Core will conduct a large-scale, whole-genome mutagenesis program to screen for recessive mutations in the third progeny generation. The primary screen will be to mater mice; females that fail to become pregnant and males that fail to make females pregnant will be subjected to a secondary screen that includes gonad histology and assessment of sperm and egg function. Heritability of reproductive defects will be confirmed by the Core and sperm from carrier males will be archived by cryopreservation. Mutants will be made available to the scientific community via the Program Project Website and the distribution facilities of The Jackson Laboratory. Mutations affected gametogenesis will be mapped in Project by Schimenti to facilitate colony maintenance and as a first step in gene cloning. The focus on Project by Schimenti will be on mutations affected meiotic recombination and chromosome metabolism; these will be mapped in Project by Schimenti to facilitate colony maintenance and as a first step in gene cloning. The focus of Project by Schimenti will be on mutations affecting meiotic recombination and chromosome metabolism; these will be mapped to high resolution and a subset will be positionally cloned. Projects by Handel and Eppig will carry out phenotype analysis of mutants impaired in spermatogenesis or sperm function, and in oogenesis or oocyte function, respectively. Additionally, a set of marker gene sequences will be developed in Projects providing a resource of molecular analysis of gametogenesis and germ cell-somatic cell communication. These marker genes will be essential for profiling gene expression during gametogenesis in mutants, providing a molecular phenotype that gives information about stage of arrest as well as of downstream sequences of mutant gene actions. Taken together, the mutagenesis program, mapping and detailed mutant phenotype analyses will provide to the scientific community unparalleled resources for understanding mammalian gametogenesis and bringing new understanding to causes of human infertility
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