Molecular assignment for two developmental mutations in the mouse

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DESCRIPTION (provided by applicant): These investigations promise to enhance research activity at CCSU by providing undergraduate and master's-level students with a variety of defined projects focused on the molecular assignment and further characterization of two pleiotropic developmental models in mice: mshi and fr. mshi, for male sterility and histoincompatibility. Males homozygous for the mshi mutation are completely sterile due to spermatogonial dysgenesis. The mshi mutation appears to identify a discrete disruption in the die-or-differentiate decision of spermatogonial stem cells at puberty, and may provide a valuable animal model for studying entry-into-spermatogenesis. In addition, mshi appears to exemplify a new type of minor histocompatibility locus that has resulted from the mutation of a single, highly-conserved gene, and mediates an unusual, cytotoxic-T-cell- independent graft-rejection mechanism. We have identified a 0.65 Mb region that must contain the mshi mutation and includes only 8 genes. Here we propose to screen these 8 candidate genes to allow cloning and sequencing of the mshi mutation. Access to the molecular gene will be used to advance our understanding of the functional role of the mshi-encoded gene product in normal and mutant tissues. fr, for frizzy. Based on co-localization and phenotypic similarity, the Charles River-hairless and fuzzy rat mutations have been renamed frizzy-Charles River (frCR) and frizzy-Harlan (frH), respectively, to reflect their likely orthology with the mouse fr mutation. Interestingly, these rat variants differ from one another and from mouse fr in terms of coat morphology, postnatal mutant viability, behavior, and mutant maternal success; where frCR > frH > fr, in terms of phenotypic severity. Therefore, we suspect that each allele has a distinct mutational basis, and that the wild-type gene product contributes to a pleiotropic array of physiology. Here we propose to genetically map mouse fr to allow identification of a small number of candidate genes. We will assess this set with the goal of assigning one of these candidates as the molecular basis of mouse fr. The availability of three mutant fr alleles should facilitate the evaluation of fr candidate genes as well as the functional analysis of the various developmental processes impacted by the fr gene product. These investigations promise to enhance research activity at CCSU while advancing the molecular characterization of two mutations that disturb functions in multiple body systems. The mshi mutation disrupts sperm development and creates a barrier to graft transplantation; the fr mutation affects hair morphology and behavior, and reduces both postnatal viability and maternal success. The molecular assignment and functional analysis of the various processes impacted by these genes may lead to rational therapies (for male sterility or alopecia, e.g.) and/or methods for regulating the function of some of these physiological systems.