This NIMH Career Development (K02) proposal is an integral part of a commitment by the applicant to discover fundamental mechanisms of brain development and to ultimately apply these basic principles to understanding psychiatric illnesses which have a genetic or developmental component. The candidate holds a B.S. in biology from Stanford University, following which he completed M.D.-Ph.D. training through the NIH-sponsored MST Program at the University of Washington, with a Ph.D. in biochemistry for developmental research in marine invertebrates. He then completed residency training in psychiatry at the University of California, San Diego, and is a board-certified psychiatrist. After clinical training, he assumed research as a Physician Fellow of the Howard Hughes Institute at the University of California, San Diego, where his work led to the discovery and characterization of novel regulatory genes expressed in the brain. Since 1994, he has continued research in this area as a member of the faculty of the Department of Psychiatry, University of California, San Diego, and a member of the University of California, San Diego interdepartmental Program in Neurosciences. The candidate is now an independent investigator, whose fully equipped and funded laboratory has produced several published reports. The candidate's home department is extremely supportive of this research program, and the research environment in neuroscience at University of California, San Diego and affiliated institutions is among the best in the nation. The candidate has been engaged in studies of the neural transcription factor Brn-3.0 and related POU-domain factors expressed in the developing brain. The expression pattern of Brn-3.0 indicates a role in the terminal differentiation of specific neurons in the CNS and peripheral sensory system. However, the expression of Brn-3.0 in the CNS suggests that it is a downstream target of certain neuroepithelial patterning genes. Understanding the factors which regulate developmental expression of Brn-3.0 combined with knowledge of how Brn-3.0 controls downstream target genes will define a developmental pathway for the Brn-3.0-expressing neurons. The experiments proposed here include three complementary sets of experiments which will elucidate the neurodevelopmental pathway of the Brn-3.0-expressing neurons: (1) Investigate the role of Pax-3 as an upstream regulator of Brn-3.0 expression in Pax-deficient mice and by ectopic expression of Pax-3 in developing embryos. (2) Further define regulatory elements in the Brn-3.0 gene locus in transgenic mice. (3) Compare the functional DNA recognition sites of Brn-3.0 to those of other POU proteins expressed in the brain to begin to decipher the transcriptional genetic code of the nervous system.
