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 (NPC(VM)) and the striatum (NPC(STR)) 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 Mash1 induced neurogenesis from expanded NPC(VM). 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. Nurr1 over-expression increased TH levels in a dose-dependant manner within both neurons and glia, suggesting a non-neuronal-specific activation of this enzyme by Nurr1. Double infection with Nurr1 and either Ngn2 or Mash1 resulted in the production of small numbers of TH+ neurons, which were larger in size when derived from NPC(VM) compared to NPC(STR). These data provide proof of concept that over-expression 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 functional DA neurons.
Kim
Hyun-Jung
HJ
The Waisman Center and Department of Anatomy, University of Wisconsin, Madison, WI 53705, USA.
Sugimori
Michiya
M
Nakafuku
Masato
M
Svendsen
Clive N
CN
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D049109:Cell Proliferation; D003001:Cloning, Molecular; D003470:Culture Media; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology; D009474:Neurons / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011247:Pregnancy; D051381:Rats; D011917:Rats, Inbred Lew; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000201:enzymology*; D014157:Transcription Factors / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis*
D051792:Basic Helix-Loop-Helix Proteins; D003470:Culture Media; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; C499318:Ascl1 protein, rat; C539884:Nr4a2 protein, rat