Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors

Information is transmitted through the brain by cells called neurons, which are connected into specific circuits and networks. As the brain develops, several different signaling molecules control how the connections between neurons develop. If these signals occur at the wrong time or wrong place, or in the wrong amount, the neurons may not connect in the right way; this is the cause of several brain disorders. One of the signaling molecules that helps neural circuits to form in the developing brain is the Dscam protein. Having too much Dscam has been linked to neurons with enlarged presynaptic terminals. Presynaptic terminals are the parts of each neuron that send information on to the next cell, and when they are enlarged it results in the neuron not being able to communicate with other neurons in a targeted way. People with brain disorders including Down syndrome, epilepsy and possibly fragile X syndrome often have excessive amounts of Dscam. It was not known precisely how Dscam signals within neurons. Sterne, Kim and Ye have now investigated this by exploring the effects of Dscam on a group of well-known neurons in the larvae of the fruit fly species Drosophila. The presynaptic terminals of single neurons in this group were labeled in the larvae using a genetic marker. This revealed that the neurons of larvae that had been engineered to produce too much Dscam had larger presynaptic terminals than normal. Further investigation showed that for Dscam to influence how a presynaptic terminal grows, it must interact with another signaling protein called Abelson tyrosine kinase (or Abl for short). Therefore, the larger presynaptic terminals seen in larvae that produce too much Dscam are a result of the Dscam protein activating too much Abl. There are several drugs that are approved for use in humans that suppress the activity of Abl. Sterne, Kim and Ye used two of these to treat fruit fly larvae, and found that they reversed the detrimental effects of extra Dscam on the larvae's neural circuit. Furthermore, the drugs fixed neural defects in a fruit fly model designed to reproduce the symptoms of fragile X syndrome. Overall, the results presented by Sterne, Kim and Ye suggest that suppressing the abnormally high activity of the Abl protein could be a way of treating the brain disorders caused by having excessive amounts of the Dscam protein. The next step is to test whether Dscam and Abl interact in the same way in mammals and whether the proposed treatment is effective in treating mammalian models of disorders that involve dysregulated Dscam signaling.