Nerve connections between the left and right hand sides of the nervous system are critically important for coordinated and independent movements. Disruption of these connections in the spinal cord can lead to curvature of the spine (scoliosis), a condition that can restrict physical activity, cause pain and lead to problems breathing. Many growing nerves in the central nervous system (CNS) make a decision whether or not to cross to the other side during embryonic development. They do this by sensing navigational cues in their environment, using specialized proteins on their cell surface known as receptors. Controlling which receptors make it to the cell surface allows neurons to control whether or not they can respond to different cues in their environment. Understanding how this process is controlled is poorly understood. In the fruit fly, "commissureless" or comm mutants have no nerve connections between their left and right sides at all. The Comm protein controls whether or not a class of receptors called Robos can make it to the cell surface. In humans, genetic variants of Robo receptors have been implicated in such diverse conditions as scoliosis and developmental dyslexia. To date, comm genes have not been found outside of insects. This proposal aims to test candidate genes from other species by using well-defined assays in fruit flies. Identification of comm genes from other species will open new avenues to studying control of receptor localization, and add to our understanding of how nerves accurately navigate long distances in the embryo. It may also help identify a novel locus for scoliosis and other disorders in which nerve wiring patterns are altered.
The commissureless gene plays a central role in nerve navigation at the CNS midline of fruit flies, yet vertebrate homologues have not been identified. This proposal aims to identify functional homologues, increasing our understanding of spinal cord development.