Functional characterization of Nurr1 and Pin1 in neuronal progenitor cell differentiation

Abstract

Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cellsduring embryonic development and it continues to be expressed in adult DA neurons. However, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study, I have used a neuronal progenitor cell line (NT2/D1), which retains some stem cell characteristics and is capable only of terminal differentiation into neurons, to analyze the function of Nurr1 in dopamine cell development. The results demonstrated that Nurr1 can induce cell cycle arrest and the cells differentiated with distinct neuronal morphology after all-trans retinoic acid treatment. It was also indicated that up-regulation of some dopaminergic neuron markers (e.g. TH, DAT and D2DR) while down-regulation of CyclinD1-Cdk6 activity marks the key events in the early stages of dopaminergic neuron differentiation. Furthermore, Pin1, a highly conserved isomerase, which directly interacts with regulators of the cell cycle, was also found to be involved in neuronal progenitor cell differentiation. Finally, the direct interaction between Nurr1 and Pin1 was identified and the possible mechanism whereby Pin1 affects the progression of cell cycle and cell differentiation by disrupting the signal transduction downstream of Nurr1-related pathway in dopaminergic neuron development was also explored.