Molecular assignment for two developmental mutations in the mouse

描述(由申请者提供)：这些研究承诺通过为本科生和硕士研究生提供各种明确的项目来加强CCSU的研究活动，这些项目的重点是小鼠的两种多效性发育模型：mshi和fr的分子分配和进一步表征。 Mshi，用于男性不育和组织不相容。Mshi突变纯合子的男性由于精原发育不全而完全不育。Mshi突变似乎识别了青春期精原干细胞死亡或分化决策的离散中断，并可能为研究进入精子发生提供一个有价值的动物模型。此外，mshi似乎是一种新类型的次要组织相容性基因，它是由单个高度保守的基因突变引起的，并介导了一种不寻常的细胞毒性T细胞非依赖性移植物排斥机制。我们已经确定了一个0.65Mb的区域，该区域必须包含mshi突变，并且只包括8个基因。在这里，我们建议筛选这8个候选基因，以便克隆和测序mshi突变。获得分子基因将有助于我们了解mshi编码的基因产物在正常和突变组织中的功能作用。 FR，代表卷曲。基于共定位和表型相似性，Charles River无毛和模糊大鼠突变已分别重命名为Frizy-Charles River(FRCR)和Frizy-Harlan(FRH)，以反映它们与小鼠fr突变的可能同源性。有趣的是，这些大鼠变种在毛形态、出生后突变体的生存能力、行为和突变母体的成功方面彼此不同，也不同于小鼠fr；其中，FRCR和FRH；fr；fr的表型严重程度不同。因此，我们怀疑每个等位基因都有不同的突变基础，并且野生型基因产物有助于多效性的生理阵列。在这里，我们建议对小鼠的fr进行基因定位，以便识别少量的候选基因。我们将评估这个集合，目标是指定其中一个候选作为小鼠fr的分子基础。三个突变的fr等位基因的可获得性应该有助于fr候选基因的评估以及fr基因产物影响的各种发育过程的功能分析。这些研究有望加强CCSU的研究活动，同时推进扰乱多个身体系统功能的两个突变的分子表征。Mshi突变会扰乱精子发育，并对移植造成障碍；fr突变会影响毛发形态和行为，并降低出生后的生存能力和产妇的成功率。对这些基因影响的各种过程的分子分配和功能分析可能会导致合理的治疗(例如，男性不育或脱发)。和/或用于调节这些生理系统中的一些的功能的方法。

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.