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 molecule s implicated in midbrain dopaminergic determination, including FGF receptor s 1, 2 and 3, the sonic hedgehog receptor components, Smo and Ptc, and the region-specific transcription factors Ptx3 and Nurrl. Here we use undiffere ntiated progenitors to probe the events leading to the dopaminergic phenoty pe and find that the influences of Nurrl can be temporally and mechanistica lly uncoupled from the patterning influences of sonic hedgehog and FGF-8 or the more generic process of neuronal differentiation itself. In gain-of-fu nction experiments, Nurrl is able to activate transcription of the tyrosine hydroxylase gene by binding a response element within a region of the tyro sine 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. Overexp ression of Nurrl does not affect proliferation or stimulate neuronal differ entiation and has no influence on the expression of other dopaminergic mark ers. This uncoupling of tyrosine hydroxylase expression from other dopamine rgic markers suggests that the midbrain dopaminergic identity is dictated b y a combination of pan-dopaminergic (e.g., Shh/FGF-8) and region-specific ( Nurrl) mechanisms.