Common sense

Formation of the mature nervous system requires axons to navigate to their correct targets and establish synaptic connections. Growing axons produce highly motile structures, called growth cones, which guide the axon to its target. They do this by responding to specific guidance molecules that either attract or repel the growth cone. The idea that axons are guided principally by molecular determinants, rather than mechanical determinants such as cells, extracellular material and other neurons, was established by Roger Sperry in 1963. However, it was not until more recent times — through the discovery of guidance molecules such as netrins, semaphorins, ephrins and Slits — that Sperry's chemoaffinity hypothesis became widely accepted as a common mechanism for guidance of not just axons, but of all cells.

In 1981, Sperry received the Nobel Prize for Physiology or Medicine “for his discoveries concerning the functional specialization of the cerebral hemispheres”. He studied patients with epilepsy in whom the corpus callosum — the bundle of axons fibres that connects the two brain hemispheres — had been severed to prevent seizures. A number of tests revealed how the two brain hemispheres hold independent streams of conscious awareness, perceptions, thoughts and memories and, importantly, that neuronal connections are formed and maintained with a high degree of precision. Having demonstrated that the establishment of specific neuronal connections is fundamental to function, Sperry turned to look at how connections are made, and used his chemoaffinity hypothesis to explain how axons find the correct target.

Others had raised the possibility that chemical determinants might function in axon guidance, but it was Sperry that provided the direct histological evidence and proposed the chemoaffinity hypothesis for axon guidance. In a series of elegant experiments using the retinotectal system of the newt, he sectioned the optic nerves and rotated the eyes 180 degrees. He wanted to know whether vision would be normal following regeneration or whether the animal would forever view the world 'upside down'. If the latter held true, this would show that the nerves were somehow guided back to their original sites of termination; however, restoration of normal vision would mean that the nerves had terminated at new sites. Sperry showed that these animals did indeed view the world 'upside down'. It was these studies that led Sperry to propose that “intricate chemical codes under genetic control” guide axons to their targets — his chemoaffinity hypothesis.

In his original hypothesis, Sperry proposed that different cells bear distinct cell-surface proteins that serve as markers — an idea that required an unsatisfactorily large number of proteins. He subsequently revised his model to suggest that dual gradients of guidance cues in the afferent and target fields would allow correct axon targeting. There is now extensive experimental data to support the chemoaffinity hypothesis, and the requirement for gradients of receptor and/or ligand (such as ephrins and Eph receptors) in both the projection and target regions is well established. Although certain aspects and details of Sperry's model are unproven or incorrect, the basic notion of the chemoaffinity hypothesis has now become dogma in developmental neurobiology.