The wiring of nerve cells is a complicated process. The cerebral cortex alone contains at least 10 billion neurons, with 60 trillion synapses linking them. Connecting up these cells is thus finely controlled. Gradually, though, research – including that of Professor Christine Holt (University of Cambridge) and colleagues – is identifying key mechanisms in axon guidance.

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Axon growth is guided by 'push and pull' mechanisms. The growing tips of axons (growth cones) are repelled from certain areas and attracted towards others.

A protein called Slit2, for example, repels growth cones of frog retinal axons. Professor Holt's group found that Slit2 led to a burst of protein synthesis in the growth cone, increasing levels of an actin regulatory protein, cofilin. This led to the dismantling of actin filaments, suggesting that changes to the internal skeleton of the cell are important in controlling the direction of axon growth.

Other work has focused on links between morphogenesis and axon guidance. For example, a protein known primarily as a gene regulator – Engrailed-2 – was also found to affect growth cones when present outside the cell, again by stimulating new protein synthesis. Interestingly, extracellular Engrailed-2 repels some neurons but attracts others.

Other morphogens, including two members of the Wnt family of proteins, are also known to guide axon growth. With colleagues in Spain, Professor Holt has shown that a probable inhibitor of Wnt signalling, SFRP1 (secreted Frizzled-related protein 1), acting through a receptor known as Frizzled-2 (Fz2), also plays a role in axon guidance.

So, as well as patterning the body, morphogens may also be important in wiring the developing nervous system.

Image: Staining of a single retinal ganglion cell, showing its long thread-like axon; Christine Holt

External links

• Piper M et al. Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 2006;49(2):215–28.
• Brunet I et al. The transcription factor Engrailed-2 guides retinal axons. Nature 2005;438(7064):94–8.
• Rodriguez J et al. SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor. Nat Neurosci 2005;8(10):1301–9.