Specification of neurotransmitter identity by Phox2 proteins in neural crest stem cells

We have investigated the specification of noradrenergic neurotransmitter id entity in neural crest stem cells (NCSCs). Retroviral expression of both wi ld-type and dominant-negative forms of the paired homeodomain transcription factor Phox2a indicates a crucial and direct role for this protein (and/or the closely related Phox2b) in the regulation of endogenous tyrosine hydro xylase (TH) and dopamine-beta hydroxylase (DBH) gene expression in these ce lls. In collaboration with cAMP, Phox2a can induce expression of TH but not of DBH or of panneuronal genes. Phox2 proteins are, moreover, necessary fo r the induction of both TH and DBH by bone morphogenetic protein 2 (BMP2) ( which induces Phox2a/b) and forskolin. They are also necessary for neuronal differentiation. These data suggest that Phox2a/b coordinates the specific ation of neurotransmitter identity and neuronal fate by cooperating environ mental signals in sympathetic neuroblasts.