Gene regulatory logic of dopamine neuron differentiation

Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York 10032, USA.
Nature (Impact Factor: 41.46). 04/2009; 458(7240):885-9. DOI: 10.1038/nature07929
Source: PubMed


Dopamine signalling regulates a variety of complex behaviours, and defects in dopamine neuron function or survival result in severe human pathologies, such as Parkinson's disease. The common denominator of all dopamine neurons is the expression of dopamine pathway genes, which code for a set of phylogenetically conserved proteins involved in dopamine synthesis and transport. Gene regulatory mechanisms that result in the direct activation of dopamine pathway genes and thereby ultimately determine the identity of dopamine neurons are poorly understood in all systems studied so far. Here we show that a simple cis-regulatory element, the dopamine (DA) motif, controls the expression of all dopamine pathway genes in all dopaminergic cell types in Caenorhabditis elegans. The DA motif is activated by the ETS transcription factor AST-1. Loss of ast-1 results in the failure of all distinct dopaminergic neuronal subtypes to terminally differentiate. Ectopic expression of ast-1 is sufficient to activate the dopamine pathway in some cellular contexts. Vertebrate dopamine pathway genes also contain phylogenetically conserved DA motifs that can be activated by the mouse ETS transcription factor Etv1 (also known as ER81), and a specific class of dopamine neurons fails to differentiate in mice lacking Etv1. Moreover, ectopic Etv1 expression induces dopaminergic fate marker expression in neuronal primary cultures. Mouse Etv1 can also functionally substitute for ast-1 in C. elegans. Our studies reveal a simple and apparently conserved regulatory logic of dopamine neuron terminal differentiation and may provide new entry points into the diagnosis or therapy of conditions in which dopamine neurons are defective.

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    • "In C. elegans, Ast-1 is indispensable to the development of dopaminergic neurons, by driving the expression of genes that determine dopaminergic cell fate, such as tyrosine hydroxylase (Th). Etv5 might serve a similar function in mammals, as is indicated by its ability to drive the expression of Th in vitro [7]. However, while Ast-1 is vital to dopaminergic development in C. elegans, Etv5 expression in the VTA/SNpc is only detectable after birth, well after the development of the dopaminergic system. "
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    ABSTRACT: Several genome-wide association studies have implicated the transcription factor E-twenty- six version 5 (Etv5) in the regulation of body mass index. Further substantiating the role of Etv5 in feeding behavior are the findings that targeted disruption of Etv5 in mice leads to decreased body weight gain and that expression of Etv5 is decreased in the ventral tegmental area and substantia nigra pars compacta (VTA/SNpc) after food restriction. As Etv5 has been suggested to influence dopaminergic neurotransmission by driving the expression of genes that are responsible for the synthesis and release of dopamine, we investigated if expression levels of Etv5 are dependent on nutritional state and subsequently influence the expression levels of tyrosine hydroxylase. While it was shown that Etv5 expression in the VTA/SNpc increases after central administration of leptin and that Etv5 was able to drive expression of tyrosine hydroxylase in vitro, AAV-mediated gene transfer of Etv5 into the VTA/SNpc of rats did not alter expression of tyrosine hydroxylase in vivo. Moreover, AAV-mediated gene transfer of Etv5 in the VTA/SNpc did not affect measures of energy balance or performances in a progressive ratio schedule. Thus, these data do not support a role for increased expression of Etv5 in the VTA/SNpc in the regulation of feeding behavior.
    PLoS ONE 04/2014; 9(4):e94159. DOI:10.1371/journal.pone.0094159 · 3.23 Impact Factor
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    • "LGII: ida-1::gfp(inIs179) (Zahn et al., 2004); LGIII: lin-39fosmid::gfp(w- gIs18) (Zhong et al., 2010; Sarov et al., 2012), cat-1::GFP(otIs221) (Flames and Hobert, 2009); LGIV: tph-1::gfp(zdIs13) (Clark and Chiu, 2003), flp-22::gfp(ynIs50) (Kim and Li, 2004); LGV: tph-1::mCherry(cccIs1), tph-1::cfp(bxIs16) (Yang et al., 2007), bas-1::GFP(otIs226) (Flames and Hobert, 2009); LG unknown: flp-21:: gfp(ynIs80), lin-11fosmid::gfp(wgIs62) (Zhong et al., 2010; Sarov et al., 2012), cat-4::gfp(otIs225). cccIs1 was made using a tph-1 prom :: mCherry transcriptional fusion (Pocock and Hobert, 2010). The construct was injected into N2 worms and integrated using a Stratagene UV Stratalinker 1800 at a setting of 300 microjoules  100. "
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    ABSTRACT: Background: Reproduction in animals requires development of distinct neurons in each sex. In C. elegans, most ventral cord neurons (VCNs) are present in both sexes, with the exception of six hermaphrodite-specific neurons (VCs) and nine pairs of male-specific neurons (CAs and CPs) that arise from analogous precursor cells. How are the activities of sexual regulators and mediators of neuronal survival, division, and fate coordinated to generate sex-specificity in VCNs? Results: To address this, we have developed a toolkit of VCN markers that allows us to examine sex-specific neurogenesis, asymmetric fates of daughters of a neuroblast division, and regional specification on the anteroposterior axis. Here, we describe the roles of the Hox transcription factors LIN-39 and MAB-5 in promoting survival, differentiation, and regionalization of VCNs. We also find that the TALE class homeodomain proteins CEH-20 and UNC-62 contribute to specification of neurotransmitter fate in males. Furthermore, we identify that VCN sex is determined during the L1 larval stage. Conclusions: These findings, combined with future analyses made possible by the suite of VCN markers described here, will elucidate how Hox-mediated cell fate decisions and sex determination intersect to influence development of neuronal sex differences.
    Developmental Dynamics 02/2014; 243(1):C1. DOI:10.1002/dvdy.24043 · 2.38 Impact Factor
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    • "By virtue of their roles in gene control, Ets-members have been found to exhibit key roles in vertebrate and invertebrate development and human disease [37]–[39]. In particular, ETV1 is known to contribute to the formation of dopaminergic neurons through the regulation of various dopamine transport and synthesis genes and also contributes to formation of proper connections between group 1a sensory afferents and motor neurons [38], [39]. In pathology, ETV1 functions in Ewing’s sarcomas through a fusion with the Ewing’s sarcoma gene (Ews) and promotes the metastasis of prostate cancer (reviewed in Oh et al., 2012) [40]. "
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    ABSTRACT: Members of the plakophilin-catenin sub-family (Pkp-1, -2, and -3) facilitate the linkage of desmosome junctional components to each other (e.g. desmosomal cadherins to desmoplakin) and the intermediate-filament cytoskeleton. Pkps also contribute to desmosomal stabilization and the trafficking of its components. The functions of Pkps outside of the desmosome are less well studied, despite evidence suggesting their roles in mRNA regulation, small-GTPase modulation (e.g. mid-body scission) during cell division, and cell survival following DNA damage. Pkp-catenins are further believed to have roles in the nucleus given their nuclear localization in some contexts and the known nuclear roles of structurally related catenins, such as beta-catenin and p120-catenin. Further, Pkp-catenin activities in the nuclear compartment have become of increased interest with the identification of interactions between Pkp2-catenin and RNA Pol III and Pkp1 with single-stranded DNA. Consistent with earlier reports suggesting possible nuclear roles in development, we previously demonstrated prominent nuclear localization of Pkp3 in Xenopus naïve ectoderm ("animal cap") cells and recently resolved a similar localization in mouse embryonic stem cells. Here, we report the association and positive functional interaction of Pkp3 with a transcription factor, Ets variant gene 1 (ETV1), which has critical roles in neural development and prominent roles in human genetic disease. Our results are the first to report the interaction of a sequence-specific transcription factor with any Pkp. Using Xenopus laevis embryos and mammalian cells, we provide evidence for the Pkp3:ETV1 complex on both biochemical and functional levels.
    PLoS ONE 01/2014; 9(1):e86784. DOI:10.1371/journal.pone.0086784 · 3.23 Impact Factor
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