중뇌 도파민신경세포 발달과정에서의 Nurr1과 Foxa2의 상호작용에 관한 연구

Abstract

The acquirement of dopamine (DA) phenotypes is a hallmark of the differentiation and functional maturation of midbrain DA (mDA) neurons, lack of which leads to the neurodegenerative disorder Parkinson’s disease (PD). Understanding how this step is achieved is important for bioassays and cell replacement therapy for PD. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a repressor protein complex with CoREST and HDAC1, an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expressions of Nurr1 and Foxa2 were established in mDA neuron progenitor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST/HDAC1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is related with open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.