| Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs which change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's Disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D{dollar}sb1{dollar} receptors. The induced mRNAs include both novel and previously described genes, with diverse timecourses of expression. Some genes are expressed at near-maximal levels within 30 minutes, while others show no substantial induction until 2 hours or more after stimulation. Some of the induced genes, such as CREM, CHOP and MKP-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, though in distinct straital cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to a variety of dopaminergic manipulations. Further analysis of the novel gene ania-6 shows that it is a member of a novel family of evolutionarily conserved cyclins. In striatal cell culture, induction of ania-6 is not blocked by the protein synthesis inhibitor cycloheximide, indicating that it is an immediate-early gene. Ania-6 has two major splice variants, which appear to be independently regulated; cycloheximide alone induces the shorter mRNA, but not the longer mRNA. The 3{dollar}spprime{dollar} untranslated region of the mRNA is highly conserved between species and may involved in the rapid degradation of ania-6 mRNA. Ania-6 may be involved in transcriptional control, since the sequence has multiple nuclear localization signals, and the most closely related genes of known function are involved in transcriptional control. |
