This blog is currently on hiatus owing to work commitments. Whilst I still keep an eye on the goings on at RiAus, and contribute to the work of the good folks at eLife, little will be added to this blog for the foreseeable future. Simon Says remains open for business, albeit at a reduced capacity. Thanks for stopping by, and I hope the archive of content found here will prove to be of interest.

Monday, 17 June 2013

Monday Science: Gangnam Style vs Neuroscience

In our office there is a filing cupboard that cannot be opened. Once, a long time ago, it was closed and locked, and the key has long since disappeared. Nobody knows who closed it. Nobody knows who has the key. But somewhere this key does exist.

In kitchen drawers across the world, there are loose keys, whose keyhole has been lost to human knowledge. Sometimes we try an unknown key in an unopened lock, wiggling it around in the vain hope of finding a match, but ultimately we usually find disappointment.

Our knowledge of biology can be just as mismatched. The ‘lock and key’ analogy is often used to describe biological concepts to describe two molecules that fit together to make something happen. The key molecule fits into the lock molecule, opening the biological door: to use scientific terms, the ligand fits into (or on to) the receptor protein, triggering downstream signalling — think of a free-floating molecule pushing a big red button on a cell, causing the cell to light up. The problem is, we’re aware of many keys and many locks, but all too often we can’t find a match. We call the unassigned receptors ‘orphan receptors’.

One such orphan receptor is called Ptp10D but, because that’s a boring name, I’m going to call it Psy, like the bloke who rides invisible horses. Now a group of scientists led by Professor Kai Zinn at the California Institute of Technology, have worked out what the key is to getting Psy excited, leading to full-on, no holds barred nervous system development.

Zinn's team took as many unknown keys as they could, and tried them in the Psy lock. To do this in biology, specifically at the microscopic level of cell biology, you need to use a few tricks and tools. Enter my good friend the fruit fly, in which a genetic tool called the Gal4/UAS system has been introduced. Don’t worry about the jargon, all you need to know is that it allows you to increase the amount of a protein (in this case the potential keys) in very specific settings. When they increased the amount of one key, which is called Sas, they found that an enzyme-linked form of Psy started to glow, the very signal they were looking for that suggested an interaction.

Sas is a protein that is normally found on nerve cells and another cell type called the glia, which are responsible for building and maintaining the nerves. Psy is also found on nerves, and — biologically speaking — it’s connected to what amounts to an ‘off’ switch (it’s called a phosphatase). When Psy is switched on, other processes switch off, much like when music snobs are turned off by Gangnam Style. So what does Sas–Psy do?

All the way down the middle of the ventral nerve cord, the fly equivalent of the spinal cord, there are two three-lane carriageways of long nerves. Certain types of nerves come off of this motorway, like slip roads, and jut away on the same side of the body. Others have to cross the motorway to eventually reach a distant part of the body, like a motorway junction roundabout that exits in all directions, including on the far side of the busy road. The biology behind crossing the middle of the road — the middle of the body’s symmetry axis — is rather complex, because nerves need to be attracted to the middle, and then repelled away.

When buckets of Sas are thrown at a fly embryo, nerves behave normally, not crossing the midline motorway when they shouldn’t. Remember, Psy is an off switch, so it doesn’t matter how many times you insert and turn the key, Psy will keep things in check. So the researchers threw buckets of Sas at a fly embryo while simultaneously taking Psy away. This time, nerves frequently crossed the midline when they shouldn't. The stereotypical patterns of the glia, those supporting cells, were interrupted as well.

Sas–Psy, then, is just one of the interactions required for the correct formation of the nervous system. The locations of Psy and Sas show how glia communicate with nerves during development. Sas is also known to work through two well-known proteins called Notch and Numb, which are involved in seemingly everything when it comes to controlling, maintaining and — potentially — rebuilding the nervous system. Sas and Psy are just two proteins, but they quickly show themselves to be amongst a tangle at the heart of building the rather complex nervous system.

There may be one key and one lock, but there are many doors.

Lee, H.-K. et al. Interactions between a Receptor Tyrosine Phosphatase and a Cell Surface Ligand Regulate Axon Guidance and Glial-Neuronal Communication. Neuron 78, 813-826 (2013)
doi: 10.1016/j.neuron.2013.04.001

See also:

Hidalgo, A. & Griffiths, R. Coupling glial numbers and axonal patterns. Cell Cycle 3, 1116-1118 (2004)
doi: 10.4161/cc.3.9.1090
Kato, K. et al. The Glial Regenerative Response to Central Nervous System Injury Is Enabled by Pros-Notch and Pros-NFκB Feedback PLoS Biol. 9, e1001133 (2011).
doi: 10.1371/journal.pbio.1001133

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