A central question in developmental neurobiology is how regulators of transcription cooperate to produce the many diverse phenotypes of developing neurons. The applicant proposes to study this issue for the striatum, a major forebrain region in the mammalian brain. The striatum has a 2 compartment (striosome and matrix) structure, and during development, neurons of the 2 compartments acquire different neurochemical phenotypes. Preliminary studies in striatal slice culture show that expression of the immediate-early gene product Fos and phosphorylation of the cAMP regulated element binding protein (CREB) can be detected at the cellular level in cultures, and suggest that Fos and CREB are regulated differently in striosome and matrix cells by activation of dopamine D1 receptors and L-type voltage sensitive channels. Further slice culture experiments are proposed to identify the molecular basis of this difference and to examine the possibility that these differences in dopamine/cAMP and calcium signaling could influence the developing phenotypes of neurons in the 2 compartments and to determine whether MAP kinase cascades are also differentially regulated in striatal compartments by calcium and dopamine. Experiments will also be done to test the effects on striatal phenotypic development of activating retinoid RXRF and retinoic acid RARB receptors, which are strongly expressed in the developing striatum, by using RXR and RAR family selective ligands in explant and slice culture experiments and testing for retinoid/cAMP interactions. Finally, a novel gene, which was cloned from striatum and which encodes both cAMP binding and Ras-family guanine nucleotide exchange factor motifs, will be characterized, with the view that this gene's protein product might serve as a direct means for dopamine/cAMP modulation of MAP kinase signaling in striatum. The long- term goal is to understand the roles of neurotransmitters and growth and differentiation factor signaling cascades in controlling the expression of striatal phenotype.
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