Columbia Researcher Turns Gonad Cells into Neurons

by rob

Digital Art by Neutrix on Deviant Art

Have you ever wondered how all the different types of cells in your body come from a single zygote cell? Every cell in your body contains a complete copy of your genetic code. The DNA in your skin cells is identical to the DNA in your liver cells, and all your other cells. So, how do all the different cell types come about? The key is transcription factors, proteins that interact with certain regions of DNA and cause them to be expressed, or prevent their expression, based on a variety of factors. Depending on which DNA segments are expressed, the cell will develop certain traits, which in turn make it become a specific type of cells. For example, neuron cells generate dendrites and axons, which connect to other neurons, while skin cells are more concerned with being structurally rigid and moving to the body's exterior. What if this wasn't a one-way street? What if you could make cells change form, regenerate, or invent new types of cells entirely?

Oliver Hobert of Columbia University and his team studied the gene regulatory logic of neuronal diversification. To better understand this mechanism, neuroscientists frequently use a humble, yet important species of worm called C. Elegans. This is essentially the 'hello world' of neuroscience. The C. Elegans worm has a mere 302 neurons and ~5000 synapses (connections between neurons) which have been carefully mapped out. Humans, by comparison, have around 85,000,000,000 neurons, and more than 1014 synapses.

Hobert et al tracked a specific neuron in the worm, ASE, basically a taste receptor. There are two, ASE-R on the right, and ASE-L on the left. This is a great example of biologal symmetry, with functional asymmetry. The same is seen in the human brain, which is biologically very symmetric, yet functionality is all spread about. So, while ASE-R and ASE-L are similar in that they are taste receptors, one recognizes positive ions of sodium, and the other recognizes negative ions of chloride. Hobert wanted to track the formation of these neurons in the developing organism, and find when they became what they are.

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The team found that symmetry develops very early. In fact, functional division was seen when the worm was only a 4-cell blastula. Importantly, they were also able to track the 'terminal selector genes', which are the transcription factors controlling the cell's development route. If you turn on, or express these genes, you can control what the cell becomes. To study gene expression researchers commonly attach a sequence called GFP, which does nothing but glow green, allowing one to visually see gene expression. The researchers increased the amount of CHE-1, the protein causing the ASE neuron information to be expressed, in an embryo and as a result many more neurons became taste receptors. It must have been a very picky eater.

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Now modifying the worm's development is one thing, but what if it was possible for cells to change what they are in an adult? The team tried introducing more CHE-1 in an adult worm, but it had no effect. After the cells had developed, modifying the terminal selection factor did nothing. However, the team later found that if they repress a certain complex called lysine-27, and then added the terminal selection factor, the adult worm's cells would suddenly change form. They found they could change healthy tissue in to muscle, or neurons. The worm's gonads even began to turn in to neurons, growing axons and dendrites. This is fascinating stuff. I'd love to see the research extended to mammalian cells, in which the vast majority of genes are weakly expressed, or unexpressed entirely.

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For more see Hobert's page here:
http://biochemistry.hs.columbia.edu/labs/hobert/whatweworkon.html
The paper is here:
Patel et al., Removal of Polycomb Repressive Complex 2 Makes C. elegans Germ Cells Susceptible to Direct Conversion into Specific Somatic Cell Types, Cell Reports (2012), http://dx.doi.org/10.1016/j.celrep.2012.09.020