The elegant logic of dopamine

Apr 22 2009 Published by under Neuroscience

First of all, you all should know that there is a new blog for all you quitters out there. And by quitters, I mean those who have quit smoking, those who want to, and those who work with them. It's run by the insightful DuWayne, a soon-to-be-ex-smoker, and sounds like a great idea. He's looking for people who want to join the quitters, or people who are already quitters. So if you're a quitter, or want to be one, saunter on over and check it out.
Secondly, Sci has found a paper. She got it through the kind offices of PhysioProf, who reads the Tables of Contents from Nature about 20 minutes before Sci does, every single time. I DO read them, I swear!!!
Anyway, this paper. It's elegant, it's beautiful, and I love it. It's some intense stuff, but I'm going to do my best, because this paper explains so much about how the dopamine system works. It's a piece, if it takes off and is replicated, that is going to change the way we think about things, and give us new targets to combat dopamine disorders such as Parkinson's. In other words, it's HOT. Flames and Hobert "Gene regulatory logic of dopamine neuron differentiation" Nature, 2009.

I write about dopamine a lot. Most particularly, I write about the subpopulation of dopamine neurons that run in the mesolimbic pathway, the pathway connected with the initial rewarding and reinforcing properties of stimuli, otherwise known as the path that gets you high (we think). But actually, there are several populations of dopamine neurons in the central nervous system, and they arise from several different subsections of cells.
Now, dopamine neurons may arise from various populations of cells, but they all DO the same thing; produce dopamine. This means that, to be a dopamine neuron, you must be able to make all of the proteins required for dopamine synthesis and transport. Of course, technically speaking, ALL neurons, and indeed all cells, have the ability to synthesize and transport dopamine, because they all have the same genes, but the reality is a bit more complicated. Each type of cell in your body expresses a very specific set of proteins for its function. This process is controlled by the regulation of genetic expression. Depending on the factors around when a cell differentiates, and the inputs it receives throughout its lifetime, certain genes will be expressed, while others will be repressed. The many factors that regulate gene expression in various types of cells still need a LOT of study, and it adds another layer of complexity to the mass complexity that is one single, tiny cell.
So anyway, back to dopamine. To be a dopamine neuron, a neuron has to express five specific genes coding for the synthesis of dopamine and its transport.

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.
Model 1: In this model, each of the separate genes required for the differentiation of a dopamine neuron would be regulated by a different set of regulatory factors. Five required genes, at least five sets of regulatory factors. What this means is that, depending on where the dopamine neuron differentiated from, it COULD have different sets of regulatory factors controlling dopamine gene expression, and you'd still end up with a dopamine neuron. For example, in neuron set A, factors A, B, and C control the expression of cat-1, cat-2, and dat-1, while in neuron set B, factors D, E, and F, control the expression of the same genes.

This isn't at all parsimonious, but the most parsimonious explanation isn't ALWAYS the correct one. Evolution goes for what works, not necessarily what's pretty, and as the neurons differentiate from different sources, it wouldn't be surprising to find different regulatory factors involved.
Model 2: This model is the more parsimonious model. It states that each of the five genes involved would be regulated by the SAME set of regulatory factors, no matter what neuron group it's from.

You can see that this model is the one that's by far the most simple. And so this is the model that the researchers in this study set out to test. After all, this is the one that is the most easy to falsify. If you knock out a regulatory factor known to regulate, say, cat-1, and dat-1 is still intact afterward, you can probably say that the two have different regulatory facotrs. Model 2, disproven, we can all go home and start figuring out the complicated version.
And that's what they did. Using the nematode worm C. elegans, they knocked out the "dopamine motif" of the transcription factor known as AST-1. And sure enough, the worms ended up with no dopamine neurons at all, they completely failed to differentiate. Then, they took worms with no AST-1, and added some in, and watched dopamine neurons differentiate where there had been none before! Simple, elegant, and what do you know, model 2 was right. Just one motif in one transcription factor was required to differentiate dopamine neurons.
Of course, that was in worms. But vertebrates (like us and mice and things) have a similar dopamine motif, activated by the transcription factor Etv-1. So the researchers took mice, knocked out Etv-1 in a specific subpopulation of neurons, and found out that, in those neurons without Etv-1, dopamine neurons failed to differentiate. Not only that, but squirting Etv-1 onto a neuronal cell culture was enough to induce dopaminergic differentiation!
I can't even tell you how lovely this study is. Not only was the experimentation elegant (a single experiment, giving you a yes or no answer to a given hypothesis), the researchers took care to do it in worms, mice, and neuronal cell culture, implying that this is a mechanisms preserved across species. In this case, the most parsimonious, elegant answer was indeed the correct one.
And it shows that dopamine differentiation follows a distinct and simple regulatory logic. You don't have to express fifty transcription factors to get all of your dopamine neurons working, you only have to express one. This has a lot of implications for dopaminergic diseases. Now that we know that only one regulatory element is required, we can narrow our search for therapies, without having to worry that we've missed another regulatory element that could be controlling the specific problem at hand. It also makes it a lot easier to find targets to induce dopamine neuron differentiation (which is a definite boon for treatment of something like Parkinson's), as you'd only have to add one regulatory element instead of 10 or more. This study is lovely, both for being simple and elegant, and for providing some much-needed, critical information that could drastically affect how we pursue new therapies. Hot.
Flames, N., & Hobert, O. (2009). Gene regulatory logic of dopamine neuron differentiation Nature, 458 (7240), 885-889 DOI: 10.1038/nature07929

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