NURR1 IS ESSENTIAL FOR THE INDUCTION OF THE DOPAMINERGIC PHENOTYPE AND THE SURVIVAL OF VENTRAL MESENCEPHALIC LATE DOPAMINERGIC PRECURSOR NEURONS

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system , including developing and mature dopaminergic neurons, Recent studies have demonstrated that Nurr1 Is essential for the induction of phenot ypic markers of ventral mid-brain dopaminergic neurons whose generatio n is specified by the floor plate-derived morphogenic signal sonic hed gehog (SHH), but the precise role of Nurr1 in this differentiative pat hway has not been established, To provide further insights into the ro le of Nurr1 in the final differentiation pathway, we have examined the fate of dopamine cell precursors in Nurr1 null mutant mice. Here we d emonstrate that Nurr1 functions at the later stages of dopamine cell d evelopment to drive differentiation of ventral mesencephalic late dopa minergic precursor neurons, In the absence of Nurr1, neuroepithelial c ells that give rise to dopaminergic neurons adopt a normal ventral loc alization and neuronal phenotype characterized by expression of the ho meodomain transcription factor and mesencephalic marker, Ptx-3, at emb ryonic day 11.5, However, these late precursors fail to induce a dopam inergic phenotype, indicating that Nurr1 is essential for specifying c ommitment of mesencephalic precursors to the full dopaminergic phenoty pe, Further, as development progresses, these mid-brain dopamine precu rsor cells degenerate in the absence of Nurr1, resulting in loss of Pt x-3 expression and a concomitant increase in apoptosis of ventral midb rain neurons in new-born null mutant mice, Taken together, these data indicate that Nurr1 is essential for both survival and final different iation of ventral mesencephalic late dopaminergic precursor neurons in to a complete dopaminergic phenotype.