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.

Scientists Find Key Signal that Guides Brain Development

Scientists at The Scripps Research Institute (TSRI) have decoded an important molecular signal that guides the development of a key region of the brain known as the neocortex. The largest and most recently evolved region of the brain, the neocortex is particularly well developed in humans and is responsible for sensory processing, long-term memory, reasoning, complex muscle actions, consciousness and other functions.

“The mammalian neocortex has a distinctive structure featuring six layers of neurons, and our finding helps explain how this layered structure is generated in early life,” said Ulrich Mueller, chair of TSRI’s Department of Molecular and Cellular Neuroscience and director of the Dorris Neuroscience Center at TSRI.

The discovery, which appears in the August 7,2013 issue of Neuron, also is likely to aid research on autism, schizophrenia and other psychiatric conditions. “With studies such as this one, we’re starting to understand the normal functions of molecules whose disruption by gene mutations can cause developmental brain disorders,” Mueller said.

Finding Their Proper Place

The signal uncovered by Mueller’s team is one that helps guide the migration of baby neurons through the developing neocortex. Such neurons are born from stem-like cells at the bottom of the neocortex, where it wraps around a large, fluid-filled space in the brain called ventricle. The newborn neurons then migrate upward, or radially away from the ventricle, being directed to their proper places in the neocortex’s six-layered, columnar structure by—among others—special guide cells called Cajal-Retzius (CR) cells.

Decades ago, scientists discovered a key signaling protein, reelin, which CR cells secrete and baby neocortical neurons must detect to migrate properly. (Mutant mice that lack a functional form of the protein show, among other abnormalities, a reeling gait—thus the name.) There have been hints since then that CR cells and baby neocortical neurons exchange other molecular signals, too. “But in many years of study, no one has been able to find these other signals,” said Mueller.

However, in a study published in 2011, Mueller and his laboratory colleagues found a significant clue. Reelin, they discovered, guides neuronal migration at least in part by boosting baby neurons’ expression of a generic cell-adhesion molecule, cadherin2 (Cdh2). Since Cdh2 can be expressed by almost any cell type in the developing neocortex, the team then began to look for other factors that would account for the specificity of the interaction between CR cells and migrating baby neurons.

An Interesting Pattern

One set of candidates were the nectins—cell-adhesion proteins known to work with cadherins in other contexts. Lead author Cristina Gil-Sanz, a senior research associate in the Mueller laboratory, mapped the expression levels of the four known types of mammalian nectin proteins in the developing mouse cortex and found an interesting pattern. “We observed that nectin1 is expressed specifically by CR cells and nectin3 by migrating neurons,” said Gil-Sanz. “At the same time, we knew from previous research that nectin1 and nectin3 are preferred binding partners.”

Gil-Sanz and her colleagues followed up with other experiments and soon confirmed that the hookup of nectin1 on CR cells with nectin3 on baby neurons is essential for proper neuronal migration. “This showed for the first time the importance of direct contacts between CR cells and migrating neurons,” Gil-Sanz said.

The experiments also showed that this direct nectin-to-nectin connection is effectively part of the reelin signaling pathway, since reelin’s promotion of Cdh2’s function in migrating neurons turns out to work largely via nectin3. “This helps explain how the interaction occurs specifically between neurons and CR cells, and doesn’t involve other nearby cells that also express Cdh2,” she said.

New Possibilities

The finding points to the possibility of other cell-specific pairings that work via generic Cdh2-to-Cdh2 adhesions in brain development. “We know that there are four nectin proteins, plus a slew of nectin-like molecules,” said Mueller. “We think that there are others that do this as well, and we’re hoping to find them.”

The new study represents a big step toward the full scientific understanding of neuronal migration in the neocortex, and it is likely to be relevant to the study of developmental brain diseases too. Reelin-signaling abnormalities in humans have been linked to autism, depression, schizophrenia and even Alzheimer’s, and, in recent years, cadherin protein mutations also have been linked to disorders including schizophrenia and autism. “Studies like ours provide insight into such findings, by showing that these molecules, in cooperation with nectins, regulate key developmental processes such as the positioning of neurons in the neocortex,” said Mueller.

By studying how birds master songs used in courtship, scientists at Duke University have found that regions of the brain involved in planning and controlling complex vocal sequences may also be necessary for memorizing sounds that serve as models for vocal imitation.

In a paper appearing in the September 2012 issue of the journal Nature Neuroscience, researchers at Duke and Harvard universities observed the imitative vocal learning habits of male zebra finches to pinpoint which circuits in the birds’ brains are necessary for learning their songs.

Knowing which brain circuits are involved in learning by imitation could have broader implications for diagnosing and treating human developmental disorders, the researchers said. The finding shows that the same circuitry used for vocal control also participates in auditory learning, raising the possibility that vocal circuits in our own brain also help encode auditory experience important to speech and language learning.