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Abstract
Experiments in mice deficient for Nurr1 or expressing the dominant-negative FGF receptor (FGFR) identified orphan nuclear receptor Nurr1 and FGFR1 as essential factors in development of mesencephalic dopaminergic (mDA) neurons. FGFR1 affects brain cell development by two distinct mechanisms. Activation of cell surface FGFR1 by secreted FGFs stimulates proliferation of neural progenitor cells, whereas direct integrative nuclear FGFR1 signaling (INFS) is associated with an exit from the cell cycle and neuronal differentiation. Both Nurr1 and INFS activate expression of neuronal genes, such as tyrosine hydroxylase (TH), which is the rate-limiting enzyme in dopamine synthesis. Here, we show that nuclear FGFR1 and Nurr1 are expressed in the nuclei of developing TH-positive cells in the embryonic ventral midbrain. Both nuclear receptors were effectively co-immunoprecipitated from the ventral midbrain of FGF-2-deficient embryonic mice, which previously showed an increase of mDA neurons and enhanced nuclear FGFR1 accumulation. Immunoprecipitation and co-localization experiments showed the presence of Nurr1 and FGFR1 in common nuclear protein complexes. Fluorescence recovery after photobleaching and chromatin immunoprecipitation experiments demonstrated the Nurr1-mediated shift of nuclear FGFR1-EGFP mobility toward a transcriptionally active population and that both Nurr1 and FGFR1 bind to a common region in the TH gene promoter. Furthermore, nuclear FGFR1 or its 23-kDa FGF-2 ligand (FGF-2(23)) enhances Nurr1-dependent activation of the TH gene promoter. Transcriptional cooperation of FGFR1 with Nurr1 was confirmed on isolated Nurr1-binding elements. The proposed INFS/Nurr1 nuclear partnership provides a novel mechanism for TH gene regulation in mDA neurons and a potential therapeutic target in neurodevelopmental and neurodegenerative disorders.
Highlights
Nurr1 and FGFR1 are integrative nuclear factors participating in postmitotic dopaminergic neuron development
FGFR1 is ubiquitously expressed within the developing and the adult CNS [13, 36], Nurr1 expression is restricted to specific areas
The nuclear localization of FGFR1 in postmitotic ventral midbrain neurons observed in this study is consistent with previous observations in postnatal rats showing that in dopamine neurons of the substantia nigra, nuclear FGFR1 co-localizes with its transcriptional partner CREB-binding protein (CBP) [14]
Summary
Nurr and FGFR1 are integrative nuclear factors participating in postmitotic dopaminergic neuron development. Results: Both nuclear receptors show a functional interaction in co-immunoprecipitation, FRAP, ChIP, and luciferase gene reporter assay. Conclusion: Cooperation of nuclear FGFR1 and Nurr offers a new mechanism in transcriptional regulation and integration. Significance: This mechanism may channel diverse stimuli in developing and mature dopaminergic neurons, providing a potential therapeutic target
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