Identification of<i>Dlk1, Ptpru</i>and<i>Klhl1</i>as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Jacobs, Frank M. J.; Linden, Annemarie J. A. van der; Wang, Yuhui; Oerthel, Lars von; Sul, Hei Sook; Burbach, J. Peter H.; Smidt, Marten P.

doi:10.1242/dev.037556

Cited by 94 publications

(113 citation statements)

References 52 publications

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“…This analysis identified 19 genes that are regulated by both Pitx3 and En1, six of which were previously identified as Nurr1 target genes (Jacobs et al, 2009b;Jacobs et al, 2011) (Fig. 3C).…”

Section: Research Articlementioning

confidence: 85%

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

et al. 2013

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Mesodiencephalic dopaminergic (mdDA) neurons control locomotion and emotion and are affected in multiple psychiatric and neurodegenerative diseases, including Parkinson’s disease (PD). The homeodomain transcription factor Pitx3 is pivotal in mdDA neuron development and loss of Pitx3 results in programming deficits in a rostrolateral subpopulation of mdDA neurons destined to form the substantia nigra pars compacta (SNc), reminiscent of the specific cell loss observed in PD. We show here that in adult mice in which the gene encoding a second homeoprotein, engrailed 1 (En1), has been deleted, dramatic loss of mdDA neurons and striatal innervation defects were observed, partially reminiscent of defects observed in Pitx3-/- mice. We then continue to reveal developmental crosstalk between En1 and Pitx3 through genome-wide expression analysis. During development, both En1 and Pitx3 are required to induce expression of mdDA genes in the rostrolateral subset destined to form the SNc. By contrast, Pitx3 and En1 reciprocally regulate a separate gene cluster, which includes Cck, demarcating a caudal mdDA subset in wild-type embryos. Whereas En1 is crucial for induction of this caudal phenotype, Pitx3 antagonizes it rostrolaterally. The combinatorial action of En1 and Pitx3 is potentially realized through at least three levels of molecular interaction: (1) influencing each other’s expression level, (2) releasing histone deacetylase-mediated repression of Nurr1 target genes and (3) modulating En1 activity through Pitx3-driven activation of En1 modulatory proteins. These findings show how two crucial mediators of mdDA neuronal development, En1 and Pitx3, interact in dopaminergic subset specification, the importance of which is exemplified by the specific vulnerability of the SNc found in PD.

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Section: Research Articlementioning

confidence: 85%

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

et al. 2013

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“…−/− mice (Jacobs et al, 2009a). Conditional knockout of Foxa1/2 during development drastically reduces Nurr1 expression (Ferri et al, 2007), probably by a direct expression control, but possibly owing to general developmental defects in the knockout mice.…”

Section: Development Analysis Of Nurr1mentioning

confidence: 99%

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Rhee

et al. 2014

Development

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Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Coexpression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoRESTHdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.KEY WORDS: Foxa2, Nurr1, Midbrain dopamine neuron, Development, Neural precursor cell, Epigenetic control, CoREST, Hdac, Mouse INTRODUCTIONMidbrain dopamine (mDA) neurons play important roles in voluntary movement, emotion and reward-based behaviors. Dysfunction or degeneration of this neuronal subtype is related to major neuropsychiatric disorders such as Parkinson's disease (PD), schizophrenia and drug addiction. Owing to the pathophysiological implications, mDA neurons are the most extensively studied cells. A molecular understanding of mDA neuron development is of high clinical interest as replacing this cell population in diseased brains is considered to be one of the most promising therapeutic approaches for PD (Deierborg et al., 2008;Morizane et al., 2008). In addition, developmental information can be exploited to establish optimal bioassays for mDA neuron-related disorders. mDA neurons arise from floor plate cells at the ventral midline of the embryonic midbrain (Bonilla et al., 2008;Ono et al., 2007). Sonic hedgehog (Shh), secreted initially by the notochord and later by floor plate cells, induces expression of forkhead family of winged-helix transcription factor 2 (Foxa2; also known as hepatocyte nuclear factor 3 beta), in the midbrain floor plate cells [mouse embryonic day (E) 8.5] (Ang et al., 1993;Monaghan et al., 1993;Placzek, 1995;Sasaki and Hogan, 1994;Sasaki et al., 1997). Foxa2 acts as a master regulator to induce expression of developmental factors specifying mDA neuron precursors such as Nurr1, Pitx3, Lmx1a, Msx1, neurogenin 2 and Mash1 (Ascl1 -Mouse Genome Informatics) (Ang, 2009;Ferri et al., 2007;Kittappa et al., 2007;Lee et al., 2010;Metzakopian et al., 2012). The early inductive role of Foxa2 is probably achieved by cooperation with the Wnt-Lmx1a/b regulatory loop from the isthmic organizer (Chung et al., 2009;Naka...

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“…The reciprocal relationship between Pitx3/RA and the expression of Dlk1 potentially reflects an important role for endogenous RA signaling in DA neurons of the SNc. Next to the effect of RA treatment on Th, Dlk1 and D2R expression, we verified the extent to which RA treatment affected the expression of other Nurr1 and Pitx3-dependent genes (Jacobs et al, 2009a;Jacobs et al, 2009b) involved in mdDA function. We found that expression of Vmat2 (Slc18a2 -Mouse Genome Informatics), Dat (Slc6a3 -Mouse Genome Informatics) and Ahd2, all downregulated in the absence of Pitx3, cannot be rescued by embryonic supplementation of RA.…”

Section: Introductionmentioning

confidence: 98%

“…In this study, we aimed to pinpoint the molecular effects of RA on gene transcription in Pitx3-deficient mdDA neurons and provide evidence for a relationship between Pitx3/RA and the expression of Dlk1, Th and D2R (Drd2). Interestingly, Dlk1 was recently identified as a novel Nurr1 target gene (Jacobs et al, 2009b). The reciprocal relationship between Pitx3/RA and the expression of Dlk1 potentially reflects an important role for endogenous RA signaling in DA neurons of the SNc.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons

et al. 2011

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SUMMARYDevelopment of meso-diencephalic dopamine (mdDA) neurons requires the combined actions of the orphan nuclear receptor Nurr1 and the paired-like homeobox transcription factor Pitx3. Whereas all mdDA neurons require Nurr1 for expression of Th and survival, dependence on Pitx3 is displayed only by the mdDA subpopulation that will form the substantia nigra (SNc). Previously, we have demonstrated that Pitx3 -/-embryos lack the expression of the retinoic acid (RA)-generating enzyme Ahd2, which is normally selectively expressed in the Pitx3-dependent DA neurons of the SNc. Restoring RA signaling in Pitx3 -/-embryos revealed a selective dependence of SNc neurons on the presence of RA for differentiation into Th-positive neurons and maintenance throughout embryonic development. Whereas these data are suggestive of an important developmental role for RA in neurons of the SNc, it remained unclear whether other Nurr1 and Pitx3 target genes depend on RA signaling in a manner similar to Th. In the search for genes that were affected in Pitx3-deficient mdDA neurons and restored upon embryonic RA treatment, we provide evidence that Delta-like 1, D2R (Drd2) and Th are regulated by Pitx3 and RA signaling, which influences the mdDA terminal differentiated phenotype. Furthermore, we show that regulation of Ahd2-mediated RA signaling represents only one aspect of the Pitx3 downstream cascade, as Vmat2, Dat, Ahd2 (Aldh1a1), En1, En2 and Cck were unaffected by RA treatment and are (subset) specifically modulated by Pitx3. In conclusion, our data reveal several RA-dependent and -independent aspects of the Pitx3-regulated gene cascade, suggesting that Pitx3 acts on multiple levels in the molecular subset-specification of mdDA neurons.

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Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Cited by 94 publications

References 52 publications

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

Specification of dopaminergic subsets involves interplay of En1 and Pitx3

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons

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