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PMID:19287374

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Citation

Flames, N and Hobert, O (2009) Gene regulatory logic of dopamine neuron differentiation. Nature 458:885-9

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.

Links

PubMed PMC2671564 Online version:10.1038/nature07929

Keywords

Animals; Caenorhabditis elegans/cytology; Caenorhabditis elegans/genetics; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Cell Lineage/genetics; Cells, Cultured; Conserved Sequence/genetics; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dopamine/metabolism; Evolution, Molecular; Gene Expression Regulation/genetics; Heat-Shock Response; Mice; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Neurogenesis/genetics; Neurons/cytology; Neurons/metabolism; Olfactory Bulb/cytology; Olfactory Bulb/metabolism; Regulatory Sequences, Nucleic Acid/genetics; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:Q22355

involved_in

GO:0071542: dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00087839
WB:WBVar00145865
WB:WBVar00241603

P

Seeded From UniProt

complete

CAEEL:Q22355

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00087839
WB:WBVar00145865
WB:WBVar00241603

P

Seeded From UniProt

complete


See also

References

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