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Molecular assignment for two developmental mutations in the mouse

小鼠两种发育突变的分子分配

基本信息

批准号：
7252908
负责人：
THOMAS R KING
金额：
$ 21.03万
依托单位：
CENTRAL CONNECTICUT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：这些调查承诺，以提高研究活动在CCSU提供本科和硕士水平的学生与各种定义的项目集中在分子分配和进一步表征的两个多效性发育模型在小鼠：mshi和fr。用于雄性不育和组织不亲和性。 mshi突变纯合子的男性由于精原细胞发育不全而完全不育。 mshi突变似乎确定了青春期精原干细胞死亡或分化决定的离散中断，并可能为研究进入精子发生提供有价值的动物模型。此外，mshi似乎是一种新型的次要组织相容性位点，该位点是由一个高度保守的单一基因突变引起的，并介导一种不寻常的、不依赖细胞毒性T细胞的移植排斥机制。我们已经确定了一个0.65 Mb的区域，必须包含mshi突变，只包括8个基因。在这里，我们建议筛选这8个候选基因，以允许克隆和测序的mshi突变。对分子基因的获取将有助于我们进一步了解mshi编码的基因产物在正常和突变组织中的功能作用。 FR，表示卷曲。基于共定位和表型相似性，查尔斯河无毛大鼠突变和模糊大鼠突变已分别更名为卷曲查尔斯河（frCR）和卷曲哈伦（frH），以反映它们与小鼠fr突变可能的直系关系。有趣的是，这些大鼠变体在皮毛形态、出生后突变体活力、行为和突变体母体成功方面彼此不同，并且与小鼠fr不同;其中在表型严重性方面，frCR> frH> fr。因此，我们怀疑每个等位基因都有不同的突变基础，野生型基因产物有助于生理学的多效性。在这里，我们建议遗传地图小鼠fr允许少数候选基因的识别。我们将评估这一组的目标分配这些候选人之一的分子基础的小鼠fr。可用性的三个突变fr等位基因应有利于fr候选基因的评价，以及由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，同时推进两种干扰多体系统功能的突变的分子表征。 mshi突变会破坏精子发育，并对移植物移植造成障碍; 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母体成功率。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。