Cilia function in spine development and disease

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Abstract/Project Summary Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the underlying cause(s) of this condition are poorly understood. Adolescent IS (AIS) commonly develops during the rapid growth phase in adolescence, leading to disfigurement, reduced pulmonary functions and chronic pain. We recently demonstrated that defects in cerebrospinal fluid (CSF) flow underlie the development of AIS in a zebrafish model. Defects in ptk7, mutations in which are causative of IS in humans, or in genes important in cilia motility, disrupt CSF flow in zebrafish. This results in the formation of scoliotic curves during a rapid growth phase in juvenile zebrafish, mimicking the onset of this disorder in humans. We demonstrate that prevention of scoliosis in this model can be achieved by expressing wildtype genes products only in motile ciliated lineages in zebrafish. Importantly, we have used a temperature sensitive cilia motility mutant to demonstrate that zebrafish can recover from the onset of scoliotic curves if cilia motility is restored in a critical time window. In this proposal, we will take the next logical step by investigating how CSF flow is sensed and how the fish responds to this information. We will investigate the role of ciliated CSF sensing neurons in the spinal canal in the development of scoliotic curves in our IS model. We will determine if the recently identified POC5 gene in human IS causes defects in CSF generation or sensation as our model would predict. We will characterize the spatial requirements for motile cilia in our model, and determine if the immune response we detect impacts spinal curve progression. At the conclusion of this work, we will have needed insights into the mechanism underlying the development and progression of spinal curvatures in response to altered CSF flow. This information is crucial for exploration of strategies to limit, or prevent, human AIS.