Gene regulatory logic of dopamine neuron differentiation

Abstract

Neurons that produce dopamine as a neurotransmitter control a broad variety of brain functions, including motor control, cognition, motivation and pleasure. How precursor cells converge onto the dopaminergic fate across the vast diversity of developmental lineages involved in those functions has been unclear. Nuria Flames and Oliver Hobert now report that the regulatory protein AST-1 is necessary and sufficient to drive and maintain the terminal differentiation of dopaminergic neurons in the nematode C. elegans. As the protein and its terminal differentiation function are strikingly conserved in mice, the results have direct implications for stem-cell replacement strategies in dopamine-related disorders such as Parkinson's disease. The authors reveal that the regulatory protein AST-1 is necessary and sufficient to drive and maintain the terminal differentiation of dopaminergic neurons in C. elegans. Because the protein and its terminal differentiation function are strikingly conserved in mice, the results have direct implications for stem-cell replacement strategies in numerous dopamine-related disorders, such as Parkinson's disease. 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.