2013
DOI: 10.1242/dev.094565
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Abstract: 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 wh… Show more

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Cited by 75 publications
(121 citation statements)
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“…The lack of En1 or Pitx3 could in part account for the low levels of Th observed in this population, despite the presence of Nr4a2 and Foxa2, known drivers of Th expression (Kadkhodaei et al, 2009;Kim et al, 2003;Pristerà et al, 2015;Stott et al, 2013;Yi et al, 2014). In accordance with this, En1 and Pitx3 have been shown to be upstream of Th, and Pitx3 has been shown to potentiate the action of Nr4a2 on the Th promoter by releasing SMRT/HDAC-mediated repression (Jacobs et al, 2009;Veenvliet et al, 2013). Although this population expresses low levels of Th, there still remains the possibility that PMv neurons might have some DA-synthesis capacity under specific environmental or physiological conditions.…”
Section: Discussionmentioning
confidence: 72%
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“…The lack of En1 or Pitx3 could in part account for the low levels of Th observed in this population, despite the presence of Nr4a2 and Foxa2, known drivers of Th expression (Kadkhodaei et al, 2009;Kim et al, 2003;Pristerà et al, 2015;Stott et al, 2013;Yi et al, 2014). In accordance with this, En1 and Pitx3 have been shown to be upstream of Th, and Pitx3 has been shown to potentiate the action of Nr4a2 on the Th promoter by releasing SMRT/HDAC-mediated repression (Jacobs et al, 2009;Veenvliet et al, 2013). Although this population expresses low levels of Th, there still remains the possibility that PMv neurons might have some DA-synthesis capacity under specific environmental or physiological conditions.…”
Section: Discussionmentioning
confidence: 72%
“…Embryonic loss of En1 leads to an early reduction of rostral DA neurons. Interestingly, gene expression profiling of these mutants reveals the upregulation of the marker Pitx2 (Veenvliet et al, 2013). Utilizing a conditional overexpressor mouse model, our data reveals that En1 is sufficient to expand DA production into the Dbx1 + mdFP, partly at the expense of STN and PM neurons.…”
Section: Discussionmentioning
confidence: 83%
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“…One direct target of PITX3 is the Aldh1a1 gene (aldehyde dehydrogenase-1a1, or Ahd2), which increases retinoic acid and upregulates Th and Drd2 (dopamine receptor 2) but decreases Dlk1 (delta-like 1 homolog) in anterior mDA cells (Jacobs et al, 2011). PITX3 also works independently of retinoic acid to upregulate Vmat and DAT and downregulate Cck (cholecystokinin) and En1/2 (Jacobs et al, 2011;Veenvliet et al, 2013) (Table 1). Moreover, Nurr1 and Pitx3 regulate each other (Jacobs et al, 2009;Volpicelli et al, 2012) and are required for the maintenance of adult mDA neurons (Kadkhodaei et al, 2009;van den Munckhof et al, 2003).…”
Section: Differentiation and Survival Of Mda Neuronsmentioning
confidence: 99%
“…Moreover, Nurr1 and Pitx3 regulate each other (Jacobs et al, 2009;Volpicelli et al, 2012) and are required for the maintenance of adult mDA neurons (Kadkhodaei et al, 2009;van den Munckhof et al, 2003). Interestingly, Nurr1 also regulates En1 (Sousa et al, 2007), which in turn regulates Pitx3, Aldh1a1, Th, Slc18a2/Vmat2, Slc6a3/Dat, Cck and Nts contributing to the proper induction of distinct mDA subsets (Veenvliet et al, 2013) (Table 1). Moreover, EN1/2 enhances the translation of mitochondrial complex I subunits and promotes the survival of adult mDA neurons in models of PD in vivo (Alvarez-Fischer et al, 2011).…”
Section: Differentiation and Survival Of Mda Neuronsmentioning
confidence: 99%