Serotonergic control of spine morphology

Project Summary The spine provides support to the skeleton and muscles. Adolescent idiopathic scoliosis (AIS), a deformity in which the spine curves during growth, impacts 3-4% of the population, most commonly girls. AIS causes chronic pain and disfigurement. Scoliosis also associates with congenital vertebral malformations that can be caused by defective patterning and formation of the notochord. Since we don't understand the basis of spine deformity, surgery or bracing are often only corrective measures. But these are expensive, painful, and not available to most. We aim to discover mechanisms of spine development, growth, and maintenance, including how these go wrong when curves arise, to provide a framework for treating spinal deformity. The potential role of the small molecule serotonin (5-HT) in spine morphology has been debated for many years. Removal of the pineal gland, a major source of 5-HT, causes curves in some animals, while changes in 5-HT levels occur in severe scoliosis patients. Using zebrafish, a tractable model of spinal deformity in which we have a great deal of expertise, our proposal will functionally and mechanistically link 5-HT and spine morphology. We have already discovered that loss of Tph2, a neuronal 5-HT-generating enzyme, causes significant spinal defects in zebrafish, supplying a strong premise for our work. In aim 1, we will perform spatial- and temporal- genetic perturbations to determine when and where 5-HT functions to control spine morphology. In aim 2, we will determine the roles of 5-HT in controlling Reissner fiber formation, subcommissural organ gene expression and notochord patterning, pathways known to control spine morphology. We have generated preliminary data which link 5-HT to these pathways. Our work to discover mechanisms underlying 5-HT function in spine morphology will be impactful because of the links between 5-HT and human scoliosis; thus, modulating 5-HT and related pathways may be an important avenue for non-invasive treatments.