Sociable receptors: in pairs, in groups or in a crowd

When cells migrate in the body, for instance, during development, or when neurons establish new connections, cells need to know where they are going. A ‘wrong turn’ will generally cause disease or developmental disorders. The cells take direction cues from other cells with which they interact, and which they then repel after a short period of contact. Among those direction cues are ephrin ligands, recognized by Eph receptors on the cell. Together with colleagues from the Max Planck Institute of Molecular Physiology in Dortmund, scientists at the Max Planck Institute of Neurobiology in Martinsried have discovered that Eph receptors must form groups of three or four in order to become active and transmit the signal. Furthermore, the ratio of such multimers to inactive dimers determines the strength of the cellular repulsion response. The new findings help scientists understand how cells communicate and offer a point of departure for studying diseases related to breakdowns in this guidance system.

When people get together, there is usually a lot of interaction. Our cells behave similarly. When cells grow close to each other during development, they need to communicate with the surrounding cells to establish whether they are in the right place in the organism and which cells they should connect with. This communication is especially critical in the brain, where adhesion and repulsion processes between neurons occur continuously. It is only when the right cells connect that something new can be learned, for example. Emerging tumours also must exchange information with the cells around them to be able to grow. “It is of fundamental importance to understand how cells communicate with one another”, says Rüdiger Klein, Director at the Max Planck Institute of Neurobiology. He has been studying the language of the cells for years together with colleagues in his department. Their research focuses on the so-called Eph receptors and their ephrin ligands.

Cell communication via ephrin/Eph receptors comes into play in most encounters between cells. As a result of this communication, one cell usually repels the other, which continues to grow in another direction. Many such instances of interaction guide the cell to the right place. The guidance system itself – the ephrins and Eph receptors – are found on the cell surface. When the ephrin and the Eph receptor of two opposing cells meet, they form an ephrin/Eph complex. This triggers cellular processes in one or both of the cells, which eventually cause the detachment of the ephrin/Eph complex and the repulsion of the two cells from one another.

“Many receptor systems have developed a security mechanism to prevent false alarms from triggering the cellular processes”, explains Rüdiger Klein. “A signal is only transmitted to the cell if two receptor/ligand pairs form a dimer.” However, in the case of ephrins and Eph receptors, things are different. Ephrin/Eph complexes form dimers, but often also larger groups on the cell membranes. Scientists were previously not sure how this affects repulsion and repulsive signalling strength.

The neurobiologists in Martinsried and their colleagues from the Max Planck Institute of Molecular Physiology in Dortmund have now been able to artificially trigger and study the formation of groups of Eph receptors in cell culture. The results show that the otherwise usual dimers are inactive when made up of Eph receptors. Only trimers and tetramers triggered the signals that caused cell repulsion. However, the scientists’ working hypothesis that a larger group would trigger a stronger signal turned out to be too simple. “It took us quite some time to figure out the system”, says Andreas Schaupp, first author of the study. “In fact, it is not the size of each individual group that matters, but the composition of the entire population of groups.”

The more trimers and tetramers and the fewer dimers present in the cell membrane, the stronger the repulsion signal. In contrast, a higher abundance of dimers and a smaller number of multimers produce a weaker reaction or none at all. “Thanks to this mechanism, a cell can grade its response from forcing another cell to make a U-turn to simply guiding it past at close range”, Rüdiger Klein says. This is an important step in understanding how migrating and growing cells navigate, and why this guidance system breaks down in some diseases.

Two-way traffic in the spinal cord

The progress a baby makes in the first year of life is amazing: a newborn can only wave its arms and legs about randomly, but not so long after the baby can reach out and pick up a crumb from the carpet. What happens in the nervous system that enables this change from random waving to finely coordinated movement? Scientists from the Max Planck Institute of Neurobiology in Martinsried near Munich, working with colleagues from New York and Philadelphia, have described a new type of nerve cell in mice which provides a valuable insight into this developmental phenomenon. During embryonic development, the projections from these cells grow from the spinal cord towards the brain. They may pave the way for other nerve cells which control voluntary movement and which only grow from the brain into the spinal cord after birth.

When we reach out towards an object with our hand or push our foot into a boot, our movements are coordinated and controlled by the brain. For this to be possible there must be a neural pathway for the brain to transmit instructions, for example to the foot; and also in the reverse direction, for stimuli from the surroundings of the foot to be passed back to the brain. Such neural pathways are formed when the projections (axons) grow out from nerve cells during development. Depending on the organism and the body part to be connected, the axons can grow to many centimetres in length. Rüdiger Klein and his team at the Max Planck Institute of Neurobiology investigate how the axons navigate through the body, and which molecules play a part in their pathfinding. In particular, the scientists have been focusing on the signalling molecules known as ephrins and their binding partners, the Eph receptors. Ephrins and Eph receptors are located on the surface of nerve cells, among other places, and help the growing cells find their way and locate their partner cells.

Some time ago, Rüdiger Klein and his team discovered in the mouse that ephrins and Eph receptors play a key role in the development of the neural networks which control our movements. The neurobiologists have been able to demonstrate that the ephrin/Eph system guides nerve cells which, after birth, send their axons from the brain into the spinal cord and direct voluntary movement in the arms and legs. In their investigations into axons which run in the opposite direction, namely from the spinal cord into the brain, the researchers came across a new cell type which also contained Eph receptors. “Just where the ‘descending’ axons were growing, we found the ‘ascending’ axons running in parallel”, says Rüdiger Klein. “That obviously raised the question in our minds as to how this parallel growth is controlled during development.”

Subsequent research by the neurobiologists uncovered something surprising: in contrast with the known cells, the ascending axons of the new cell type did not grow only after birth, but instead already during embryonic development. Moreover, their growth was guided by the same ephrin/Eph signalling system as that involved in the growth of the descending axons. “It would seem that during embryonic development the ascending axons would ‘pre-drill’ a channel for the descending axons which do not grow out until after birth”, explains Rüdiger Klein.

Further investigations into the new, ascending nerve cells have made it clear that they obtain their input from specialised, touch-sensitive cells. A new feedback system could thus be involved here: voluntary movements are refined by signals from touch-sensitive cells, so adapting the intended movement to the environment and your foot slips into the boot. “What we found surprising is the fact that one and the same guidance system directs both the descending and the ascending axons”, says Klein. “This is a wonderful example of how a highly complex nervous system can be built up by making flexible use of individual molecules, and thus a small number of genes.” The next job for the scientists is to find out whether the suspected feedback system actually exists, i.e. whether the ascending and descending cells are connected via synapses. Their aim is to unravel step by step the developmental processes which enable the brain to coordinate sequences of movements.