Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1

The production of dopamine (DA) neurons from neural progenitor cells (NPC) is of particular interest as these neurons degenerate in Parkinson's disease. Here, we report that the characteristics of NPC from the ventral midbrain (NPCVM) and the striatum (NPCSTR) are intrinsically determined. A detailed analysis of the VM during development revealed Ngn2 and Mash1 expression in a DA progenitor domain. Interestingly, over-expression of either Ngn2 or Mashl induced neurogenesis from expanded NPCVM. Whereas Ngn2 inhibited cell division and the production of neurons even in the presence of mitogens, Mash1 allowed the progenitors to divide while retaining neurogenic potential. However, none of the new neurons derived by over-expressing Ngn2 or Mash1 were positive for DA neuronal markers such as tyrosine hydroxylase. Nurr 1 over-expression increased TH levels in a dose-dependant manner within both neurons and glia, suggesting a non-neuronalspecific activation of this enzyme by Nurr1. Double infection with Nurr1 and either Ngn2 or Mash1 resulted in the production of small numbers of TW neurons, which were larger in size when derived from NPCvm compared to NPCSTR. These data provide proof of concept that overexpression of multiple transcription factors can drive the fate of NPC first towards neurons, and then towards the DA phenotype. However, further factors may be required to generate fully ftinctional DA neurons. (c) 2006 Elsevier Inc. All rights reserved.