Function of Mhc class lb molecules in vomeronasal organ

描述（由申请人提供）：犁鼻器（VNO）是高等脊椎动物中专门检测信息素的化学感受器官。在小鼠和大鼠中，两个基因超家族，V1 r和V2 r犁鼻受体基因，在感觉神经元中表达，其细胞体分别位于VNO上皮的顶端和基底层。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，代表非经典的主要组织相容性复合体（MHC）的I类基因。9个H2-Mv基因在神经元亚群中差异表达，并且一个以上的H2-Mv基因可以在单个神经元中表达。V2 rs和H2-Mvs分子以优选的组合共表达。H2-Mvs似乎在V2 rs向细胞表面的运输中起护送分子的作用。V2 r和H2-Mv复合物在细胞表面上的功能以及V2 r和H2-Mv组合共表达的意义尚不清楚。我建议生产小鼠品系的H2-Mv基因座和V2 r基因的靶向突变。具体目标1是通过染色体工程技术删除包含所有已知H2-Mv基因的簇，阐明H2-Mv基因家族的体内功能。犁鼻感觉神经元的轴突投射，电生理特性，以及性和社会行为将被分析。具体目的2是通过将IRES-taulacZ或IRES-tauGFP盒靶向整合到单个H2-Mv和V2 r基因中来理解H2-Mv与V2 r表达偶联的多样表达的机制和意义。犁鼻上皮和大脑之间的布线模式将被可视化，并且将测试H2-Mv和V2 r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，而且将为神经系统和免疫系统之间的相似性提供新的见解。

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.