Scientists find a completely new function for a known protein family

The cortex is  comprised of several billion nerve cells. These cells process movement and sensory information and govern speech and logical thinking. An international team led by scientists of the Max Planck Institute of Neurobiology in Martinsried was able to reveal an important mechanism for the development of this complex brain structure. The protein family known as FLRTs are located on the surface of young nerve cells, from where they regulate embryonic tissue cohesion – for example in the heart’s development. The scientists were able to show in mice that FLRT proteins have a second, so far unknown function: part of the protein can split off and bind as a ligand to the receptors of another nerve cell. This interaction leads to the repulsion of young, roaming nerve cells and helps to guide them through the cortex – an important insight into the general development of the cortex. (EMBO Journal, online publication 14. June 2011)

Masterminds like Mozart, Einstein or van Gogh owe their exceptional talents to their cortex. The nerve cells in this area also allow normal people like us to learn, speak, process sensory information and to think logically. For these activities to work at their best, it is essential that the nerve cells connect with their correct partner cells. This is no easy task, since the developing cortex is a site of intense activity: thousands of young nerve cells migrate into this area, where they either proceed directly to their target location or wait for some time before they continue on their way. Bit by bit, the typical cortex structure, consisting of layers of cell bodies, develops. Once the nerve cells have reached their destination, they extend long processes, so-called neurites into the surrounding area. They connect in part to neighboring cells and in part to cells in other cortex layers. However, in this turmoil of billions of wandering nerve cells and growing neurites, how does a cell know where to go and in which direction to send its neurites?

In yellow are young nerve cells with Unc5 receptors on their surface. When these encounter FLRT proteins (in the blue areas), the growing cell neurites retract and continue their growth in a FLRT-free area.

Proteins as growth pilots
To date, a number of surface proteins are known which guide growing nerve cells and their neurites. Scientists at the Max Planck Institute of Neurobiology, for example, have successfully revealed that the Ephrin proteins direct nerve cells via repulsion. Another group, the FLRT proteins, are surface receptors which attract other cells and lead to the cohesion of tissues.
Prior studies by the Martinsried scientists showed that embryonic tissue breaks apart when one of the three FLRT proteins is lost. The cells then continue to develop into completely different cell types. Now, the neurobiologists have shown, with the help of an international team, that FLRT proteins have another, completely different function – they aid in the orientation of nerve cells during the brain’s development.

The researchers were able to show that part of the FLRT receptor is able to split off. The thus mobile protein part can then bind to Unc5 receptors on other nerve cells. The result of this interaction was impressive: the growth cone of the filament collapsed, the filament retracted and stopped, or continued its growth in another direction. In addition to the already known attractive function of FLRT proteins, the split-off part of the protein can apparently act as a repulsive signal for nerve cells. “It is rather unusual and therefore came as a surprise that a receptor, or part of it, becomes a ligand for another receptor”, explains Rüdiger Klein, the project’s head. “It seems that the more complex an organism gets, the more tasks its individual components need to carry out.”

Guidance system in the cortex
The scientists also demonstrated the importance of the newly discovered interaction between FLRT and Unc5 for cortex development. The first layer of the developing cortex consists of nerve cells with FLRT proteins. Young nerve cells without Unc5 receptors pass through this layer without problems. In contrast, nerve cells bearing Unc5 receptors on their surface are unable to cross. They have to wait until their receptors have regressed. In the meantime, the nerve cells which were Unc5-free from the beginning have time to reach their destination in the cortex and to form a new layer. When the nerve cells with the regressed receptors migrate into the cortex, they probably have to interact with the cells of this new layer as well, before they can settle down and rebuild their receptors. In this way, the interaction between FLRT and Unc5 contributes significantly to the correct layer arrangement of the cortex. “This is an important insight which may also help us to better understand misguided development in this part of the brain”, says Rüdiger Klein.

Arturo Tenacio says: Congratulations to this international team on this fascinating finding. Hopefully it will serve to advance in the discovery of restoring guidance and, therefore function and health, for the nerve cells that, for some reason, were not able to reach their destination during the pregnancy period.