A microRNA Feedback Circuit in Midbrain Dopamine Neurons

摘要

Midbrain dopamine neurons (mDNs) play a central role in complex behaviors such as reward and addiction, and these cells are lost in Parkinson's disease (PD). A number of transcription factors have been implicated in the regulation of mDNs. However, the role of post-transcriptional mechanisms in mDNs, or in other post-mitotic neuron types, is relatively uncharacterized. Here we investigate the role of microRNAs (miRNAs) in mDN regulation in relation to previously described transcriptional control mechanisms. miRNAs are evolution-arily conserved, 18-25 nucleotide, non-protein coding transcripts that play an important function in post-transcriptional regulation of gene expression during development. In preliminary studies and a recent manuscript, we identified eight miRNA enriched in the midbrain, and one - miR-133b - as a mDN-enriched miRNA that appears to function within a feedback circuit with the homeodomain transcription factor Pitx3. miRNAs are derived from long primary transcripts through sequential processing by the Drosha ribonuclease (Lee et al. 2003) and the Dicer enzyme (Grishok et al. 2001; He and Hannon 2004). In the context of an RNA-induced silencing complex (RISC), miRNAs guide the cleavage of target mRNAs and/or inhibit their translation (Meister and Tuschl 2004). miRNAs were first characterized in invertebrates, where they function to regulate developmental cell fate decisions in the nervous system (Chang et al. 2004; Johnston and Hobert 2003) and elsewhere (Ambros 2003). In vertebrates, several hundred miRNAs have been identified, but only a few of these have been associated with specific cellular functions. For instance, the mir-430 family of miRNAs appears to be required for normal brain morphogenesis in zebrafish development (Giraldez et al. 2005, 2006).