Genetic Architecture of Behavior

Genetics of Human Diseases

Olfactomedins

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Olfactomedins and Development of the Nervous System

Olfactomedins are a large and diverse family of extracellular and membrane-associated proteins. The archetype of this family was identified in our laboratory almost 15 years ago as the primary structural component of the lower mucus layer of olfactory neuroepithelium, where its specific expression in olfactory glands and supporting cells and its close association with chemosensory cilia of olfactory receptor neurons suggested a role in the maintenance and/or differentiation of the apical dendrites of olfactory neurons. Phylogenetic analyses of olfactomedin homologues showed that olfactomedins occur widely and evolved from an ancestral gene before vertebrate evolution. During its evolution the C-terminal region (the “olfactomedin homology domain”) of about 250 amino acids was conserved and evolved relatively slowly; in contrast, the N-terminal regions of olfactomedin related proteins are vastly divergent. The Drosophila genome contains one olfactomedin, the gene product of the CG6867 gene. Caenorhabditis elegans has two olfactomedins, one expressed in coelomocytes, which represent primitive immune defense cells, and one at the neuromuscular junction. The mouse and human genomes each encode families of at least 13 olfactomedin related proteins.

Several studies have recently demonstrated important neurodevelopmental roles for olfactomedins, including assembly of the nodes of Ranvier. In collaboration with Drs. Ju-Ahng Lee and Gregory Cole at North Carolina Central University, we have shown in zebrafish that olfactomedins play a critical role in the early development of anterior spinal cord motorneurons, cranial nuclei and sensory systems, including the optic tectum, the eyes and olfactory organs. We are continuing to use the zebrafish model to assess the mechanisms by which olfactomedin regulates neural development and we will also generate conditional homologous recombinant mice to determine whether olfactomedins expressed in olfactory tissue provide signals for the differentiation of apical ciliated dendritic knobs of olfactory sensory neurons, which are the sites where odor recognition and olfactory transduction occur.

Representative publications:

Karavanich, C. A. and Anholt, R. R. H. (1998) Molecular evolution of olfactomedin. Mol. Biol. Evol. 15: 718-726.

Kulkarni, N. H., Karavanich, C. A, Atchley, W. R. and Anholt, R. R. H. (2000) Characterization and differential expression of a human gene family of olfactomedin-related proteins. Genet. Res. 76: 41-50.