Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation.
The nuclear transcription factor Nurr1 is involved in the development and maintenance of the midbrain dopaminergic (DA) neuronal phenotype. We analysed the cellular and biological effects of Nurr1 during embryonic stem (ES) cell differentiation using the ROSA26-engineered Tet-inducible ES cell line J1-rtTA that does not express transgenes in mature neurons. Induction of Nurr1 at nestin-positive precursor and later stages of ES cell differentiation produced a non-neuronal DA cell type including functional DA transporters. In these cells, we found a clear correlation between Nurr1 and TH gene expression and specific midbrain DA cellular markers such as AADC, AHD2 and calbindin. Nurr1 did not alter gene expression of non-DA neuronal phenotypes and did not influence other midbrain developmental transcription factors, such as Otx1, Otx2, En-1, GBX2, Pitx3 and lmx1b. In addition, Nurr1 expression was required for maintenance of the DA phenotype and mediated up-regulation of the tyrosine kinase Ret and associated trophic factor GDNF-family receptors alpha 1, 2, and 4. This demonstrates that Nurr1 is sufficient to induce and maintain a midbrain-like DA biochemical and functional cellular phenotype independent of neurogenesis.
Sonntag
Kai-Christian
KC
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Simantov
Rabi
R
Kim
Kwang-Soo
KS
Isacson
Ole
O
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004298:Dopamine / Q000096:biosynthesis* / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling / Q000379:methods; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D004318:Doxycycline; D004298:Dopamine