New Research Sheds Light on Wiring of the Brain
Posted on: 28 September 2010
The mechanism underlying the interaction between two proteins which control the growth and guidance of developing nerve fibres in the brain has been revealed in a new collaborative study by researchers at Trinity College Dublin and Oxford University. The research which has just been published in the leading international journal, Nature, was funded by Science Foundation Ireland.
Research in the laboratory of Dr Kevin Mitchell at the Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, has shown that a protein called ‘Sema6A’, is required for nerve cells in various parts of the brain to migrate to the correct position and make appropriate connections. The Sema6A protein is expressed on the surface of certain cells and is detected by a receptor protein called PlexinA2, on the surface of other cells. If either of these proteins is mutated then a variety of nerve tracts in the brain are wired incorrectly.
The new discovery reveals how these proteins interact with each other and the effects that this interaction has on the cell. In a collaboration with Dr Bert Janssen, Dr Ross Robinson and others in the laboratory of Professor Yvonne Jones at Oxford University, the biochemical structures of these two proteins and the nature of their interaction has been revealed at atomic-level resolution.
The brain is composed of thousands of distinct regions, which must be wired together in a very precise fashion to enable them to carry out their specific functions. This is accomplished as growing nerve fibres sense and respond to cues concerning other cells in the tissue of the developing brain, which control the direction of projection of each axon. The outer membrane of each cell is studded with protein molecules which act both as sensors, or receptors, for these cues and as cues for other cells to respond to.
The new data were obtained using X-ray diffraction crystallography, in which protein molecules are grown into densely packed crystals. X-rays are then passed through these crystals and the beams of X-rays become diffracted, or bent, as they interact with the atoms of the proteins. By analysing the pattern of the diffracted X-rays it is possible to deduce the arrangement of the atoms of the protein.
These data reveal precisely which atoms in Sema6A, on one cell, interact with particular atoms in PlexinA2 on another cell. Dr. Francesc Perez-Branguli, a postdoctoral fellow in Dr Mitchell’s laboratory at TCD, also showed that when this interaction occurs, the migration of the nerve cells expressing PlexinA2 is reduced.
Commenting on the significance of the findings, Dr Mitchell said: “The structural detail which has been revealed will also provide some leads in designing chemical agents to disrupt the interaction. This may be crucial in trying to develop therapeutic agents which can block the functions of these proteins in the adult, where their effects are not always beneficial. Sema6A functions in adults to repress excessive nerve growth – this is usually a good idea as it maintains the stability of connections in the brain.”
“Unfortunately, in the event of an injury, to the spinal cord for example, the effect of the Sema6A protein contributes to preventing the regrowth of damaged nerve fibres. The long-term goal is to design chemicals which block the interaction with the PlexinA2 receptor, which could allow nerves to ignore the signal and help them reconnect across the site of injury. While such treatments remain a long way off, and must necessarily involve many other proteins, the knowledge gained in this study brings them one step closer to a reality.”
Trinity in the News:
- Irish Times, 28th September