FACULTY

	Bruce Hamilton, Ph.D. Department of Medicine Secondary Appointments: Department of Cellular and Molecular Medicine George Palade Laboratories 9500 Gilman Drive La Jolla, CA 92093-0644 lab tel: 858-822-2298 Email: bah@ucsd.edu Lab Website: http://cmm.ucsd.edu/Lab_Pages/hamilton/bah/
CV
Research Title
Genetic Control of Neural Development and Disease
Research Description
Development and disease in the cerebellum. The cerebellum is both a significant locus of human disease and an unusually tractable brain structure for genetic analysis. Through positional cloning and gene trap studies in mice we have identified transcriptional regulators required for proliferation of cerebellar progenitors (Zfp423) and for differentiation of the cerebellar Purkinje cells (Rora). Nur12 affects the decision of neural progenitors in both the fourth ventricular zone and rhombic lip/external germinal layer to remain in the cell cycle. Loss of this transcription factor results in a vermis malformation reminiscent of human disorders. RORa is required for differentiation and maintenance of Purkinje neurons, output neurons derived from the ventricular zone. Developmental RNA profiling and chromatin immunoprecipitation experiments identify direct transcriptional targets of RORa that strongly overlap with genes affected by Spinocerebellar ataxia type 1 (SCA1), a polyglutamine repeat expansion disorder, prior to degeneration of the Purkinje cells. Genetic suppression of mRNA processing defects by a nuclear export factor. Genetic analysis of other neurological mutations has lead us to a novel mechanism of genetic suppression. Endogenous retroviruses are a frequent cause of spontaneous mutations in mice. Integrations into introns where, RNA processing signals in the provirus quantitatively interfere with the normal processing of the interrupted host gene, are particularly common. We have shown that a naturally-occuring amino acid substitution allele of the mRNA nuclear export factor Nxf1 alters the balance of alternative processing of several unrelated retrovirus mutations. Population genetics indicates that Nxf1 has recently been under strong directional selection in wild mice, plausibly in response to an infectious RNA virus. New data suggests that the human NXF1 locus has also undergone positive selection, for expression level, in the human lineage. Sympathetic control of blood pressure. Sympathetic tone at neuroeffector junctions is a key regulator of blood pressure. In a collaborative case/control study of candidate genes for genetic susceptibility to hypertension we find evidence for susceptibility conferred by a variant in one of the granins, regulators or catecholaminergic vesicle function. The risk allele confers transcriptional enhancer activity and is bound in cells by paired-like homeobox proteins.
Recent Publications
Alcaraz, W. A., Gold, D. A., Raponi, E. Gent, P. M., Concepcion, D., and Hamilton, B. A. (2006) Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation. Proc. Natl. Acad. Sci. USA 103, 19424-19429. http://www.pnas.org/cgi/content/abstract/0609184103v1 Gold, D. A., Gent, P. M., and Hamilton, B. A. (2006) RORa in genetic control of cerebellum development: 50 staggering years. (Review) Brain Res. in press http://dx.doi.org/10.1016/j.brainres.2005.11.080bstract/0609184103v1 Concepcion, D., Seburn, K., Wen, G., Frankel, W. N., and Hamilton, B. A. (2004) Mutation rate and predicted phenotypic target sizes in ENU-treated mice. Genetics 168(2), 953-959. http://www.genetics.org/cgi/content/full/168/2/953 Wen, G., Mahata, S. K., Cadman, P., Mahata, M., Ghosh, S., Mahapatra, N. R., Rao, F., Stridsberg, M., Smith, D. W., Mahboubi, P., Schork, N. J., O'Connor, D. T., and Hamilton, B. A. (2004) Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. American Journal of Human Genetics 74, 197-207. http://www.journals.uchicago.edu/AJHG/journal/issues/v74n2/40136/40136.html Gold, D. A., Baek, S. H., Schork, N. J., Rose, D. W., Larsen, D. D., Sachs, B. D., Rosenfeld, M. G. and Hamilton, B. A. (2003) RORa coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron 40, 1119-1131. http://dx.doi.org/10.1016/S0896-6273(03)00769-4 Floyd, J. A., Gold, D. A., Concepcion, D., Poon, T. H., Wang, X., Keithley, E., Chen, D., Ward, E. J., Chinn, S. B., Friedman, R. A., Yu, H.-T., Moriwaki, K., Shiroishi, T., and Hamilton, B. A. (2003) A natural allele of Nxf1 suppresses retrovirus insertional mutations. Nature Genetics 35, 221-228 http://cmm.ucsd.edu/hamilton/bah/epubs/Floyd_2003_NG.pdf Hamilton, B. A. and Frankel, W. N. (2001) Of Mice and Genome Sequence. (Minireview) Cell 107, 13-16. http://dx.doi.org/10.1016/S0092-8674(01)00514-1 Floyd, J. A. and Hamilton, B. A. (1999) Intranuclear Inclusions and the Ubiquitin-Proteasome Pathway: Digestion of a Red Herring? (Preview) Neuron 24, 765-766. http://dx.doi.org/10.1016/S0896-6273(00)81022-3 Hamilton, B. A., Smith, D. J., Mueller, K. L., Kerrebrock, A. W., Bronson, R. T., van Berkel, V., Daly, M. J., Kruglyak, L., Reeve, M. P., Nemhauser, J. L., Hawkins, T. L., Rubin, E. M. and Lander, E. S. (1997) The vibrator mutation causes neurodegeneration via reduced expression of PITPa: Positional complementation cloning and extragenic suppression. Neuron 18, 711-722. http://dx.doi.org/10.1016/S0896-6273(00)80312-8 Hamilton, B. A., Frankel, W. N., Kerrebrock, A. W., Hawkins, T. L., FitzHugh, W., Kusumi, K., Russell, L. B., van Berkel, V., Mueller, K. L., Birren, B. W., Kruglyak, L., and Lander, E. S. (1996) Disruption of nuclear hormone receptor RORa in staggerer mice. Nature 379, 736-739. http://dx.doi.org/10.1038/379736a0

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