The human nervous system is a complex network of cells, all working together. The intense specialization of this network starts during development, when cells must talk to each other to carefully coordinate wiring up neural circuitry.

The wiring relies on the neural cells themselves. They have rounded cell bodies surrounded by short spines called dendrites, and longer tails, called axons. Each neuron only has one axon, which connects to dendrites on other nerve cells.

Sending that axon to the right place—a process called neural pathfinding—is the subject of an entire field of study. Researchers have identified a variety of specialized signaling molecules that instruct neurons on where they should go. It's not always clear, however, how these signaling networks interact to send axons to the right place. A recent paper published in Science helps to clarify some of these unknowns.

In this paper, researchers have looked into the details of how signaling networks help control neural cell movements. They focused on a protein involved in axon guidance called called Robo 3.1, and helped show that it integrates both attractive and repulsive signals. The redundant nature of this signaling pathway sheds light on how axons are able to move in such precise ways: their movements are guided by attractive and repellent forces that work together to send them to the right place.

The new study examined neuron signaling using mouse cells cultured in a protein mixture that mimics their normal environment. They focused on the interactions between the NELL2 and Robo3.1 proteins. Their data indicated that when a source of NELL2 is placed near these cells, their axons change their direction, growing away from the NELL2 molecules.

In animals, NELL2 is expressed in two regions of the developing spinal column, which helps guide axons in the spine towards the correct destination. When they engineered mice that were lacking NELL2, they found these mice also had less Robo3.1 than normal—manipulation of one of these proteins can effect the other, reinforcing neural guidance signals.

In addition to this NELL2 repulsion, previous work has shown that Robo 3.1 inhibits a second neural guidance protein called Slit, and facilitates attraction to a third axon guidance protein known as Netrin. The fact that these events are mutually reinforcing ensures the needed accuracy and precision for axon guidance.

Understanding the signaling that allows neurons to send their axons to the correct destination could allow doctors to redirect nerves of transplanted tissues or in patients who have suffered serious injuries. Additionally, it could provide important insight about potential therapies for patients with nerve dysfunction or developmental disorders, some of which may be the result of aberrant neuronal guidance.

Science, 2015. DOI: 10.1126/science.aad2615 (About DOIs).