The orphan nuclear receptor Nurr1 and the transcription factor Pitx3 are key regulators of dopaminergic (DA) neuron specification in the meso-diencephalic (md) region, which has been intensively studied owing to the importance of mdDA neurons in Parkinson's disease. Now, Marten Smidt and colleagues demonstrate a functional relationship between these two factors(). The authors show that both Nurr1 and Pitx3 bind to the co-repressor PSF and that both target the same genomic promoter regions, suggesting that Pitx3 might regulate the activity of the Nurr1 transcriptional complex. Indeed, in Pitx3-/- embryos, Nurr1 target gene expression is reduced,in accordance with increased interaction between Nurr1 and the co-repressor SMRT. The researchers also succeeded in partially rescuing Nurr1 target gene expression by interfering with SMRT signalling activity. Based on these findings, the authors propose a novel model in which Pitx3 regulates the capacity of Nurr1 to induce mdDA neuron specification by inducing the release of the SMRT repressor from the Nurr1 transcriptional complex.
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