Regulation of mammalian odorant receptor gene expression

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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.