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: 42.35). 04/2009; 458(7240):885-9. DOI: 10.1038/nature07929
Source: PubMed

ABSTRACT 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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 01/2014; 243(1):C1. DOI:10.1002/dvdy.24043 · 2.67 Impact Factor
  • Source
    • "(B and C) DIC images of adult hermaphrodites (top) and corresponding epifluorescent images of the HSNs (bottom) in wild-type (B) and daf-18(ok480) mutant animals (C). HSN is visualized with a GTP cyclohydrolase GFP reporter (cat-4::gfp), which is expressed in all dopaminergic and serotonergic neurons (Flames and Hobert, 2009). Images are oriented with the posterior of the animals to the right. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration; conversely, when signaling is enhanced, DAF-16 is inactivated, and migration is inhibited. We show that DAF-16 acts nonautonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of insulin/IGF-1-DAF-16 signaling in the nonautonomous control of HSN migration. Because a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are most likely conserved from C. elegans to higher organisms.
    Cell Reports 08/2013; 4(5). DOI:10.1016/j.celrep.2013.07.045 · 8.36 Impact Factor
  • Source
    • "For example , an evolutionarily conserved DNA sequence in the regulatory regions of five DA genes ( TH , AADC , GTP cyclohydrolase ( required for synthesis of tetrahydrobiopterin , an essential co - factor for TH ) , DAT and VMAT ) is necessary and sufficient to collectively drive expression of all these genes during development , in mature DA neurons , and in non - DA neurons in C . elegans and mice ( Flames and Hobert 2009 , 2011 ) , but see ( Wang and Turner 2010 ) . Interestingly , this sequence binds members of the E - twenty six ( ETS ) family of transcription factors , which are regulated by a host of signaling cascades including those sensitive to neuronal activity and intracellular Ca 2+ ( such as PKC , CaMKs and calcineurin ( Yordy and Muise - Helmericks 2000 ) ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms of Parkinson's disease. The development of cell-replacement therapies for Parkinson's disease motor symptoms is hampered by poor acquisition and retention of the DA phenotype by endogenous and transplanted neurons. Factors which regulate the DA phenotype in the adult SNc are, therefore, keenly sought. Transcription of the rate-limiting enzyme in DA synthesis, tyrosine hydroxylase, and possibly other DA genes, is known to be regulated by changes in membrane potential and intracellular Ca²⁺. Furthermore, emerging evidence indicates DA gene transcription is sensitive to fast membrane potential changes and intracellular Ca²⁺ transients, that is, those associated with normal rates and patterns of neuronal activity. In other words, the DA phenotype is activity-dependent. In this review, we highlight the importance of spatiotemporal Ca²⁺ dynamics for regulating gene expression in cells, and the possible role of fast Ca²⁺ dynamics associated with normal rates and patterns of neuronal activity. We review evidence supporting activity- and Ca²⁺-dependent regulation of the DA phenotype in cells, including SNc neurons, as well as knowledge about the molecular pathways intervening between intracellular Ca²⁺ and TH gene expression. We describe the electrophysiology of SNc DA neurons, emphasizing features that may regulate DA gene expression. We conclude by bringing together this information in a model of how neuronal activity might regulate the DA phenotype in SNc neurons.
    Journal of Neurochemistry 02/2012; 121(4):497-515. DOI:10.1111/j.1471-4159.2012.07703.x · 4.24 Impact Factor
Show more


1 Download
Available from