Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells

Dopamine cells are generated in the ventral midbrain during embryonic devel opment. The progressive degeneration of these cells in patients with Parkin son's disease, and the potential therapeutic benefit by transplantation of in vitro generated dopamine cells, has triggered intense interest in unders tanding the process whereby these cells develop. Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. H owever, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study we have used a dopamine-synthesizing c ell line (MN9D) with immature characteristics to analyze the function of Nu rr1 in dopamine cell development. The results demonstrate that Nurr1 can in duce cell cycle arrest and a highly differentiated cell morphology in these cells. These two functions were both mediated through a DNA binding-depend ent mechanism that did not require Nurr1 interaction with the heterodimeriz ation partner retinoid X receptor. However, retinoids can promote the diffe rentiation of MN9D cells independently of Nurr1. Importantly, the closely r elated orphan receptors NGFI-B and Nor1 were also able to induce cell cycle arrest and differentiation. Thus, the growth inhibitory activities of the NGFI-B/Nurr1/ Nor1 orphan receptors, along with their widespread expression patterns both during development and in the adult, suggest a more general role in control of cell proliferation in the developing embryo and in adult tissues.