Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain.
Adult rat-derived hippocampal progenitor cells express many of the molecules implicated in midbrain dopaminergic determination, including FGF receptors 1, 2 and 3, the sonic hedgehog receptor components Smo and Ptc, and the region-specific transcription factors Ptx3 and Nurr1. Here we use undifferentiated progenitors to probe the events leading to the dopaminergic phenotype and find that the influences of Nurr1 can be temporally and mechanistically uncoupled from the patterning influences of sonic hedgehog and FGF-8 or the more generic process of neuronal differentiation itself. In gain-of-function experiments, Nurr1 is able to activate transcription of the tyrosine hydroxylase gene by binding a response element within a region of the tyrosine hydroxylase promoter necessary for midbrain-specific expression. This activation is mediated through a retinoid X receptor independent mechanism and occurs in all precursors, regardless of differentiation status. Overexpression of Nurr1 does not affect proliferation or stimulate neuronal differentiation and has no influence on the expression of other dopaminergic markers. This uncoupling of tyrosine hydroxylase expression from other dopaminergic markers suggests that the midbrain dopaminergic identity is dictated by a combination of pan-dopaminergic (e.g., Shh/FGF-8) and region-specific (Nurr1) mechanisms.
Sakurada
K
K
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Ohshima-Sakurada
M
M
Palmer
T D
TD
Gage
F H
FH
D000367:Age Factors; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D008636:Mesencephalon / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000378:metabolism; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D000099153:Pentraxins
D002097:C-Reactive Protein; D004268:DNA-Binding Proteins; D004298:Dopamine; D016222:Fibroblast Growth Factor 2; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor; D000683:Serum Amyloid P-Component; D015534:Trans-Activators; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D000099153:Pentraxins; C539884:Nr4a2 protein, rat