Ankyrin G (red) clusters at the axon initial segment of a neuron.

Neurons rely on different structures to ignite nerve impulses and to propel them along the axon. Dzhashiashvili et al. show on page 857 that these structures develop in distinct ways. One structure depends on internal signals, whereas the other receives guidance from glial cells that wrap the axon in a myelin sheath.

The two types of structures, axon initial segments (AISs) and nodes of Ranvier, are molecularly similar, carrying current-producing sodium channels, the adhesion molecule neurofascin186 (NF186), and the actin–membrane linker ankyrin G. AISs touch off an action potential, whereas the nodes relay it along the axon. Evidence suggested that the two structures formed differently, but researchers didn't know the details.

To determine how NF186 gets into place, the researchers created composites that contained part of this protein and part of ICAM1, an immune molecule that neurons don't make. The composite accumulated in AISs only if it contained the intracellular part of NF186. The results for nodes were the opposite—the hybrid proteins built up only if they sported the extracellular part of NF186. That finding suggests that the neighboring Schwann cells direct NF186 into nodes.

The researchers also showed that Ankyrin G is essential for both structures but congregates differently. It concentrates in AISs before drawing in NF186. However, NF186 is essential before nodes can attract ankyrin G. The results indicate that AISs are built from inside out, and nodes from outside in.