Growth cones, attractive and repulsive cues, Sperry's chemoaffinity hypothesis, and the molecules — netrins, slits, semaphorins, ephrins — that wire the developing brain.
Development & Plasticity
Advanced
Axon Guidance: How Neurons Find Their Partners
The Editors
April 7, 2026
2 min read
In plain English
When a new neuron grows its axon, the tip — called a growth cone — 'sniffs' its surroundings for chemical signposts that attract or repel it. Following these cues, axons travel to the right targets, sometimes across the whole brain. Then activity fine-tunes the connections.
Advanced level: The detailed machinery — ions, receptors, circuits and methods. Read the linked concepts first.
Concepts to know first
A developing axon may need to travel centimetres through a crowded, changing embryo to find its correct partners. How does it get there?
The growth cone
In the 1890s Santiago Ramón y Cajal described the growth cone, the swollen, hand-like tip of a growing axon, and guessed it was steered by chemicals. Time-lapse imaging later showed growth cones extending and retracting finger-like filopodia to explore their environment, advancing toward some signals and collapsing in response to others.
Chemoaffinity
In the 1940s Roger Sperry cut the optic nerves of frogs and newts and rotated their eyes 180 degrees. The nerves regrew to their original targets in the brain — so the animals forever after struck to the wrong side when trying to catch flies. Sperry concluded that each neuron carries a chemical identity tag and its target a matching tag — the chemoaffinity hypothesis (formalised in 1963).
The guidance molecules
Four major families of guidance cues have since been identified, each acting through specific receptors: netrins (often attractive), slits (repulsive, acting through Robo receptors), semaphorins (mostly repulsive) and ephrins with their Eph receptors (often forming gradients that map one structure onto another, such as the retina onto the midbrain). Morphogens and adhesion molecules also guide axons.
A classic example is the midline: many spinal axons are attracted to the midline by netrin, cross it, then switch on Robo receptors so that slit repels them and they never cross back.
Activity refines the map
Molecules lay down a rough map; neural activity refines it. Before birth, waves of spontaneous activity sweep across the retina and help sort connections in visual pathways — "practising" before there is anything to see. Mistakes in guidance genes contribute to some rare movement and eye disorders, and possibly to conditions such as autism.
Everyday examples & things to try
Analogy
A hiker with a scent trail
A growth cone is like a hiker in fog following scent markers: some smells say 'this way', others 'keep out'. At certain junctions the hiker even changes their sense of smell, so a marker that once attracted now repels — which is how axons cross the midline once and never return.
Key takeaways
- The growth cone explores and steers the growing axon.
- Sperry's eye-rotation experiments supported chemical matching between neurons and targets.
- Netrins, slits, semaphorins and ephrins guide axons; activity refines the final wiring.
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