Connecting Left and Right
Organisms with a bilaterally symmetric nervous system face a problem – how to integrate functions across the two sides so that behavioural outputs can be coordinated for the entire body. In the brain this is important to allow integration of the large number of cognitive “modules” which are differentially lateralised, such as language. (The importance of this communication is dramatically illustrated by so-called “split-brain” patients, who have had the majority of the connections between the two cerebral hemispheres severed in order to treat otherwise intractable epilepsy. These patients, first studied by Roger Sperry and colleagues, end up in essence with two brains inside the same skull, and it could be argued, two largely independent minds).
The importance of bilateral integration is also evident and very well understood in the control of movement, where motor commands have to be tightly and dynamically coordinated across the two sides of the body. The integration of the two sides of the nervous system is mediated by nerve fibres that project from one side to the other. Some neurons project axons across the midline and others do not – the binary nature of this choice has made it a favourite model system of developmental neurobiologists to investigate how growing axons are guided along specific pathways to their appropriate targets. As a result, a great deal is known about the cellular and molecular processes that control whether an axon will cross the midline.
The process is mediated by attractive and repulsive signals made by specialised cells which reside at the midline of the nervous system. (Interestingly, the study of such “chemotropic” molecules was also pioneered by Sperry in a set of seminal experiments in the frog visual system). These signals are detected by dedicated receptor proteins expressed on the surfaces of growing axons. The signals at the midline include two major families of secreted proteins: Netrins, which function to attract some neurons towards and across the midline, while repelling others, and Slits, which repel axons that normally do not cross the midline and which also prevent axons from re-crossing the midline multiple times. How each neuron responds to these cues depends on which receptors it expresses: DCC is a receptor protein for Netrins, while Robo proteins are receptors for Slits. Amazingly, all these proteins are very highly conserved, as are their functions in controlling axonal projections across the midline, which were discovered and elucidated in great detail in nematodes, fruit flies and mice.
A number of studies have shown that their functions are also conserved and equally crucial in humans. Elizabeth Engle and her colleagues found that mutations in the ROBO3 gene can lead to a condition with the unwieldy name of horizontal gaze palsy with progressive scoliosis (HGPPS). This syndrome is characterised by an inability to coordinate the lateral movement of the eyes in the horizontal plane. Lateral eye movements are controlled by the abducens-oculomotor nerves, one on each side of the head. The coordination of these movements of the two eyes is mediated by a set of interneurons which normally project across the midline of the hindbrain, where the cell bodies that form these nerves are located, and coordinate the activity of the nerves on the two sides.
As the ROBO3 gene is known to be required for axons to cross the midline, the implication was that the defect resulted from a failure to connect these cranial nerve nuclei on the two sides. A recent study by Alain Chedotal and colleagues modeling the effects of Robo3 mutations in mice strongly supports this explanation – deletion of the gene in just that part of the hindbrain did indeed disrupt connectivity between the two sides and resulted in similar defects in horizontal eye movements in the mice.
(If you’ve been paying attention you may be surprised that mutations in a Robo gene should cause a failure of axons to cross the midline – if the normal role of the Slit signals to which they respond is to keep axons on their own side, then mutation of a Robo gene should cause extra axons to cross the midline. This is true for the other two Robo genes – Robo3 performs a different role, down-regulating the responses of the other Robo proteins and so mutating it has the opposite effect).
Another study just published by Guy Rouleau and colleagues shows that the function of DCC in establishing trans-midline connectivity is also essential in humans. They found mutations in this gene in patients with Congenital Mirror Movements. These are involuntary movements of one side of the body that occur in response to voluntary movement of the other side – i.e., a failure to independently control and coordinate the two sides. A similar effect has been seen in mice with mutations in this gene, which are called “Kanga” mice because of their unusual hopping gait, caused by moving both hindlimbs at the same time. The mirror movements could be caused by a failure to project across the midline of interneurons in the spinal cord that normally inhibit movement of one side when the other side is moving.
These studies provide a dramatic example of the importance of bilateral integration in the control of movement. It will be interesting to investigate whether patients with these disorders also show any differences in cognitive domains which might relate to subtly altered connectivity of the two cerebral hemispheres.
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Jen, J. (2004). Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis Science, 304 (5676), 1509-1513 DOI: 10.1126/science.1096437
Renier N, Schonewille M, Giraudet F, Badura A, Tessier-Lavigne M, Avan P, De Zeeuw CI, & Chédotal A (2010). Genetic dissection of the function of hindbrain axonal commissures. PLoS biology, 8 (3) PMID: 20231872