Professor of Neurobiology*
*Coates Family Professor of Neuroscience, Helen Wills Neuroscience Institute; Head, Neuroscience Graduate Program
How does the olfactory apparatus of vertebrates detect and discriminate thousands of odors? Our approach to elucidating the mechanisms of olfactory discrimination involves the characterization of odorant receptors and the neural pathways that they activate. We are also interested in the developmental mechanisms responsible for specifying olfactory neurons and the pathfinding of these cells' axons to their appropriate targets. Finally, our lab is applying large scale gene expression approaches to elucidate genome-wide patterns of gene expression in the nervous system.
The zebrafish olfactory system. The numerical and anatomical simplicity of the zebrafish olfactory system facilitates an analysis of the molecular and cellular basis of olfactory coding in a vertebrate species. In one line of investigation, we are defining the odorant-binding properties of cloned fish odorant receptors, as fish respond to water soluble cues that are more amenable as probes for biochemical analyses. The zebrafish also offers advantages for studying development; methods for the generation and screening of mutant zebrafish may permit genetic approaches for studying odorant receptor gene expression and olfactory neurogenesis. Genomic mapping of odorant receptor genes and reveals that, as in other vertebrate species, odorant receptor genes are clustered in the zebrafish genome. However, genes tightly linked within a cluster are not coordinately regulated, suggesting that the regulation of individual receptor genes require the interaction of specific trans-acting factors with proximal cis-regulatory sequences. We are pursuing a variety of approaches, including transgenic manipulations, to define the promoter sequences responsible for directing the developmentally-regulated expression of the odorant receptor genes. We are also developing in vivo optical imaging techniques to monitor and analyze patterns of neuronal activity in response to odorant stimulation.
Patterning in the olfactory bulb. Olfactory neurons expressing the same odorant receptor converge with great precision to a small number of glomeruli in the olfactory bulb. This suggests that spatial patterns of afferent innervation in the bulb are used to encode olfactory information. What are the mechanisms for specifying the pattern of olfactory neuron projections in the olfactory bulb? We are pursuing several complementary approaches to identify the molecules involved in olfactory axon pathfinding. Transgenic manipulations in the mouse and zebrafish are being used to assess the potential role of candidate genes in the formation of the olfactory sensory map. We are also utilizing DNA microarrays to search for molecules expressed in spatially-restricted patterns in the olfactory bulb; such molecules would be good candidates as guidance cues for ingrowing olfactory axons.
Analysis of gene expression in the developing nervous system. Recent advances, which include the sequencing of entire genomes of selected model systems and the ability to survey "genome-wide" patterns of gene expression, now allow the dissection of biological processes at unprecedented levels of detail. We have established in our laboratory the full capabilities for carrying out large scale analysis of gene expression. These techniques allow the analysis of mRNA expression from tens of thousands of genes at a time. We are using genome-wide approaches as tools to investigate patterns of developmentally-regulated and spatially-restricted patterns of gene expression in the vertebrate central nervous system. Projects are focused on identifying the gene regulatory networks associated with olfactory neurogenesis during development and regeneration.
Triballeau, N., E. Van Name, G. Laslier, D. Cai, G. Paillard, P.W. Sorensen, R. Hoffman, H.O. Bertrand, J. Ngai, and F.C. Acher. 2008. High potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function. Neuron 60, 767-774.
The Cancer Genome Atlas Research Network. 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068. [Epub ahead of print, Sept 4, 2008]
Duggan, C.D., S. DeMaria, A. Baudhuin, D. Stafford, and J. Ngai. 2008. Foxg1 is required for development of the vertebrate olfactory system. J. Neurosci. 28, 5229-5239.
Scolnick, J.A., K. Cui, S. Xuan, C.D. Duggan, X.-b Yuan, A. Efstratiadis, and J. Ngai. 2008. Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57, 847-857.
Szpara, M., K. Vranizan, Y.C. Tai, C.S. Goodman, T.P. Speed, and J. Ngai. 2007. Analysis of gene expression during neurite outgrowth and regeneration. BMC Neuroscience 8, 100.
Alioto, T.S. and J. Ngai. 2006. The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids. BMC Genomics 7, 309.
Alioto, T.S. and J. Ngai. 2005. The odorant receptor repertoire of teleost fish. BMC Genomics 6, 173.
Luu, P., H.O. Bertrand, F. Acher, J. Fan, and J. Ngai. 2004. Molecular determinants of ligand selectivity in a vertebrate odorant receptor. J. Neurosci. 24, 10,128-10,137.
Lin, D.M., Y.H. Yang, J.A. Scolnick, L.J. Brunet, V. Peng, Y. Okazaki, Y. Hayashizaki, T.P. Speed., and J. Ngai. 2004. A spatial map of gene expression in the olfactory bulb. Proc. Natl. Acad. Sci. USA 101, 12,718-12,723.
Diaz, E., Y. Ge, Y.H. Yang, K.C. Loh, T. Serafini, Y. Okazaki, Y. Hayashizaki, T.P. Speed, J. Ngai, and P. Scheiffele. 2002. Molecular analysis of gene expression in the developing pontocerebellar projection system. Neuron 36, 417-434.
Last Updated 2009-07-07