Axon Guidance

Back for some more neuroscience.  Today we are going to look at axon guidance, how it is achieved, and what determines whether guidance cues are short or long range, attractive or repulsive.

First off, what is axon guidance?  Axon guidance is the process by which developing neurons send out their axons to reach targets; the axons follow certain paths to the correct target.  We are going to look at how they manage to accurately reach their target.

An axon's growth cone, the motile tip of a growing axon, acts as a sensory vehicle, detecting cues in the extracellular environment and then reacting appropriately to those cues.  Guidance cues can either attract or repel the axon.  When the growth cone senses the guidance cues, it activates a series of intracellular cascades that ultimately lead to a change in the cytoskeletal structure of the neuron.

What kinds of molecular cues will an axon encounter?  There are several, and they can be grouped into two categories: Short vs. Long-range, and Attractive vs. Repulsive.

The axon will experience both attractive and repulsive cues many times over many different ranges.  Contact attraction and repulsion  is generally associated with short-range cues via surface proteins.  Chemoattraction and repulsion is more generally associated with a longer range.  Chemical signals are secreted and diffused within a distance of about 100-500um.

A good example of a class of repulsive guidance cues is the semaphorins.  They act as axon repellents by activating complexes of cell-surface receptors called plexins and neuropilins (class 3) and integrins (class 7).








Now we are going to examine an interesting and important case, crossing the midline.  One of the most crucial periods of human brain development involves axonal crossing of the midline, the forming of the corpus collosum, the nerve bundle connecting the two hemispheres of the brain, allowing for neural communication from one side to the other.

Kim Peek (the real-life "Rain Man"), a mega-savant, was born with agenesis of the corpus collosum and a missing anterior commisure.  His reading technique consisted of reading the left page with his left eye and the right page with his right eye.  He could therefore read two pages at a time, covering them at a rate of 8-10 seconds per page.  He could recall exact information when asked directly. So why couldn't one side of Kim's brain communicate with the other?  The decision to cross or not cross the midline is critical.  Let's take a closer look.

There are three very important steps in midline crossing:
1. Getting to the midline
2. Crossing it once
3. Moving on in the opposite hemisphere

Getting to the midline.  The commisural axons get to the midline via chemoattractant guidance cues. The floor plate plays an integral role in attracting the axons via emission of netrins, guidance proteins.  Sonic HeadgeHog (Shh) also acts to guide axons toward the floor plate. Netrins secreted by the floor plate cells function to bind the axon receptor DCC in a chemotactic manner. 

Crossing it once.  A study examining the ventral nerve cord of the fly (Goodman) found that axons cross the midline through the anterior commisure (AC) or posterior commisure (PC).  Wild-type fly axons crossed the midline once and left, continuing in their development in the opposite hemisphere.  However, researchers found 3 mutants that acted to disrupt the system: slit, robo, and comm.  Slit flies saw axons remain in the midline.  Roundabout (robo) flies saw axons cross the midline, only to recross back into the original hemisphere.  Commisureless (comm) flies saw no crossing of the midline.      

Moving on.   Once across, the axons generally have a decent rate of success in moving on.  Researchers have also come up with ways to switch on certain cues at different points in the process, enabling them to "choreograph" the sequence in different ways.