The Elegant Logic Of Dopamine: Gene Expression & Dopamine Neuron Regulation
Abstract (Via Nature)
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.
Additional Interpretation Via (Neurotopia)
Here you can see the five genes that need to be expressed to produce a dopamine neuron. These genes are cat-4, which expresses GTPCH (GTP cyclohydrolase), cat-2, which expresses TH (tyrosine hydroxylase, the first enzyme in the conversion of the amino acid tyrosine to DOPA and thence to dopamine), bas-1, which expresses AAAD (aromatic amino acid decarboxylase, which converts DOPA to dopamine), cat-1, which expresses VMAT (the vesicular monoamine transporter, which controls the sequestration of dopamine into vesicles for release), and dat-1, which expresses DAT (the dopamine transporter, which recycles dopamine back into the synapse for recycling and metabolism). *poof* complete dopamine neuron.
The thing is, how do you get all of these genes to be expressed in any one neuron? How is the gene expression for this particular set of machinery controlled? Until now, it was thought that there were two possible mechanisms that could make a dopamine neuron.