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Gene regulatory logic of dopamine neuron differentiation

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 disease1. 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 far2. 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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Figure 1: Characterization of the DA motif in C. elegans.
Figure 2: ast-1 is required to induce and maintain DA neuron differentiation.
Figure 3: Ectopic ast-1 expression can induce DA cell fate.
Figure 4: Mouse Etv1 is necessary for the olfactory bulb DA neuron specification

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Acknowledgements

We thank Q. Chen for injection assistance, M. Doitsidou and J. Chen for providing the ot417 allele, E. Savner for initiating some of the promoter analysis, A. Kruyer for technical help, the CGC for strains, the C. elegans Gene Knockout Consortia, led by S. Mitani at Tokyo Women’s Medical University School of Medicine and by D. Moerman at the University of British Columbia, for knockout alleles, H. Hutter, N. Tavernarakis and T. Jessell for strains and reagents, several members of Columbia University community for sharing their equipment, Hobert laboratory members, especially M. Doitsidou, for discussion, and A. Abeliovich, R. J. Johnston and I. Greenwald for comments on the manuscript. This work was funded by the National Institutes of Health (R01NS039996-05; R01NS050266-03), the Howard Hughes Medical Institute and a EMBO long term fellowship and Marie Curie Outgoing International fellowship to N.F.

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Correspondence to Nuria Flames or Oliver Hobert.

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Flames, N., Hobert, O. Gene regulatory logic of dopamine neuron differentiation. Nature 458, 885–889 (2009). https://doi.org/10.1038/nature07929

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