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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    • "To identify candidates for transcription factors involved in the differentiation of our neuronal tissues, we performed a blast analysis for transcription factors identified in terminal selector programs, or pathways that that control the expression of identifying features of mature individual neuron types[33,6869707172. We searched for 24 different gene sequences, all of which were found within our transcriptome (e-val < 10 −4 ) (Additional file 1: Table S2). "
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    • "The type of differentiation program controlled by TTX-3 in different neuron types is specified by a distinctive combination of additional transcription factors (Wenick and Hobert 2004; Zhang et al. 2014). Similar genetic studies on other neuronal types, including AWB (Nokes et al. 2009), AWC (Kim et al. 2010), and ciliated (Swoboda et al. 2000) and dopaminergic (Flames and Hobert 2009; Doitsidou et al. 2013) neurons have generated a unique understanding of the cis and trans mechanisms that initiate single neuronal identities and are responsible for cellular diversity and organism complexity. C. elegans ASJ neurons are a bilaterally symmetric pair of ciliated sensory neurons located in the amphid, the main chemosensory organ of the nematode. "
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    Full-text · Article · Mar 2015 · Genetics
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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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