Function of Mhc class lb molecules in vomeronasal organ

Mhc lb类分子在犁鼻器中的功能

• 批准号: 6889150
• 负责人: TOMOHIRO ISHII
• 金额: $ 8.44万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889150
• 关键词: MHC class II antigen; animal communication behavior; bioengineering /biomedical engineering; chemoreceptors; electrophysiology; gene deletion mutation; gene expression; genetic recombination; genetically modified animals; laboratory mouse; neuroimmunomodulation; olfactions; pheromone; protein structure function; sex behavior; social behavior; transfection /expression vector; vomeronasal systems

DESCRIPTION (provided by applicant): The vomeronasal organ (VNO) is a chemosensory organ specialized in the detection of pheromones in higher vertebrates. In mouse and rat, two gene super families, V1r and V2r vomeronasal receptor genes, are expressed in sensory neurons whose cell bodies are located in, respectively, the apical and basal layers of the VNO epithelium. We and others have reported that neurons of the basal layer express another multigene family, termed H2-Mv, representing nonclassical class I genes of the major histocompatibility complex (Mhc). The nine H2-Mv genes are expressed differentially in subsets of neurons and more than one H2-Mv gene can be expressed in an individual neuron. V2rs and H2-Mvs molecules are co-expressed in preferred combinations. H2-Mvs appear to function as escort molecules in transport of V2rs to the cell surface. The functions of the V2r and H2-Mv complex on the cell surface, and the significance of the combinatorial coexpression of V2r and H2-Mv is not known. I propose to produce strains of mice with targeted mutations in the H2-Mv locus and in V2r genes. Specific Aim 1 is to elucidate the in vivo function of the H2-Mv gene family by deleting the cluster containing all known H2-Mv genes by the technique of chromosome engineering. Axonal projections of vomeronasal sensory neurons, electrophysiological properties, and sexual and social behaviors will be analyzed. Specific Aim 2 is to understand the mechanism and significance of variegated expression of H2-Mv coupled with V2r expression by a targeted integration of IRES-taulacZ or IRES-tauGFP cassette into individual H2-Mv and V2r genes. The wiring patterns between the vomeronasal epithelium and the brain will be visualized, and functions of H2-Mv and V2r proteins in the axon targeting and combinatorial coexpression will be tested. This study will reveal not only novel functions of the nonclassical molecules of Mhc class I, but will provide new insights into parallels between the nervous and immune systems.

描述(申请人提供)：犁鼻器(VNO)是高等脊椎动物中专门检测信息素的化学感官器官。在小鼠和大鼠中，V1r和V2r两个基因超家族在感觉神经元中表达，其胞体分别位于VNO上皮的顶层和基底层。我们和其他人已经报道，基底层的神经元表达另一个多基因家族，称为H2-MV，代表主要组织相容性复合体(MHC)的非经典I类基因。9个H2-MV基因在神经元亚群中差异表达，单个神经元可以表达多个H2-MV基因。V2Rs和H2-MVS分子以首选的组合方式共表达。H2-MVS似乎在将V2r运送到细胞表面的过程中起到护送分子的作用。V2r和H2-MV复合体在细胞表面的功能以及V2r和H2-MV组合共表达的意义尚不清楚。我建议培育出H2-MV基因和V2r基因发生定向突变的小鼠品系。特异目的1是利用染色体工程技术，通过删除包含所有已知H2-MV基因的簇，阐明H2-MV基因家族在体内的功能。本课程将分析犁鼻感觉神经元的轴突投射、电生理特性以及性行为和社会行为。具体目的2是通过将IRES-taulacZ或IRES-tauGFP盒定向整合到单独的H2-MV和V2r基因中，了解H2-MV与V2r表达的差异表达的机制和意义。我们将可视化犁鼻上皮和脑之间的连接模式，并测试H2-MV和V2r蛋白在轴突靶向和组合共表达中的功能。这项研究不仅将揭示MHC I类非经典分子的新功能，还将为神经系统和免疫系统之间的相似之处提供新的见解。