Involvement of corticotropin-releasing factor receptor 2β in differentiation of dopaminergic MN9D cells

Corticotropin releasing factor (CRF) mediates various responses to stress through CRF receptors 1 and 2. CRF receptor 2 has two forms, 2α and 2β each of which appears to have distinct roles. Here we used dopaminergic neuron-derived MN9D cells to investigate the function of CRF receptor 2 in dopamine neurons. We found that n-butyrate, a histone deacetylase inhibitor, induced MN9D cell differentiation and increased gene expression of all CRF receptors. CRF receptor 2β was minimally expressed in MN9D cells; however, its expression dramatically increased during differentiation. CRF receptor 2β expression levels appeared to correlate with neurite outgrowth, suggesting CRF receptor 2β involvement in neuronal differentiation. To validate this statement, we made a CRF receptor 2β-overexpressing MN9D/CRFR2β stable cell line. This cell line showed robust neurite outgrowth and GAP43 overexpression, together with MEK and ERK activation, suggesting MN9D cell neuronal differentiation. From these results, we conclude that CRF receptor 2β plays an important role in MN9D cell differentiation by activating the MEK/ERK signaling pathway.