Regulation of mammalian odorant receptor gene expression

哺乳动物气味受体基因表达的调节

• 批准号: 6831727
• 负责人: PETER MOMBAERTS
• 金额: $ 39.75万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-05 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831727
• 关键词: chemoreceptors; gene expression; gene rearrangement; gene targeting; genetic promoter element; genetically modified animals; laboratory mouse; neurogenetics; olfactions; polymerase chain reaction; vomeronasal systems

DESCRIPTION (provided by applicant): An experimentally tractable system for neuronal diversity is the olfactory system, which utilizes a repertoire of 1000 (OR) genes each expressed in a subset of olfactory sensory neurons (OSNs). A given OSN expresses a single OR gene, from one allele. An OSN projects a single axon that innervates a specific glomerulus in the olfactory bulb, and this choice is determined in part by the specificity of the expressed OR. Thus, central to the function of the olfactory system is the process of OR gene expression. However, twelve years after the discovery of OR genes, regulation of OR expression remains enigmatic; publications are far and few between, and are contradictory. In preliminary studies, model systems have been developed. Short transgenes impart many of the intricate features of OR gene expression. This was shown for two OR genes (MOR23 and M71) that have little sequence homology to each other and are located on different chromosomes. A 395 basepair region is required for MOR23 transgene expression. Without the Lhx2 homeodomain protein, OSNs do not differentiate terminally and M71 is not expressed. The hypothesis to be tested is that OR gene expression (and similarly, expression of vomeronasal receptor genes, two other types of chemosensory receptor genes) is controlled by short promoters that contain motifs essential for normal patterns of expression, and that are possibly altered by DNA rearrangements. The approach is genetic manipulation of the mouse: transgenesis and targeted mutagenesis. The Specific Aims are: 1: To test the function of the homeodomain motif in expression of the MOR23 endogenous gene, and to determine if Lhx2 deficiency can be rescued by M71 expression. 2: To generalize the concept of short promoters to other odorant receptor genes. 3: To determine if short transgenes of vomeronasal receptor genes are expressed. 4: To search for DNA rearrangements in odorant receptor genes. Pilot data, tools, reagents, techniques, expertise and personnel are well established in the laboratory. As mammalian brain function relies on a great many neuronal cell types, this research will contribute to our understanding of neural development and function.

描述（由申请人提供）：一种实验性的神经元多样性系统是嗅觉系统，它利用了1000（或）基因的曲目，每个曲目均在嗅觉感觉神经元（OSN）子集中表达。给定的OSN从一个等位基因中表达单个或基因。 OSN投射一个单个轴突，该轴突支配嗅球中的特定肾小球，并且该选择部分取决于表达或表达的特异性。因此，嗅觉系统功能的核心是基因表达的过程或基因表达。然而，发现或基因十二年后，调节或表达的调节仍然神秘。出版物之间很少，而且是矛盾的。 在初步研究中，已经开发了模型系统。短转基因赋予许多复杂的特征或基因表达的特征。这是针对两个或基因（MOR23和M71）的，它们彼此之间几乎没有序列同源，并且位于不同的染色体上。 MOR23转基因表达需要一个395基底区域。没有LHX2同源域蛋白，OSN不会终端区分，并且未表达M71。 要检验的假设是或基因表达（类似地，同样，呕吐受体基因的表达，另两种类型的化学感受器受体基因）受到短启动子的控制，这些短启动子包含对正常表达模式必不可少的基序，并且可能被DNA重排改变。该方法是对小鼠的遗传操纵：转基因和靶向诱变。 具体目的是：1：测试同源域基序在MOR23内源基因表达中的功能，并确定是否可以通过M71表达来挽救LHX2缺乏症。 2：将短启动子的概念推广到其他气味受体基因。 3：确定是否表达呕吐受体基因的短转基因。 4：寻找气味受体基因中的DNA重排。 试点数据，工具，试剂，技术，专业知识和人员在实验室中已建立。由于哺乳动物的大脑功能依赖于许多神经元细胞类型，因此这项研究将有助于我们对神经发育和功能的理解。