Exploring the Conservation of Idiopathic Scoliosis Symptoms from Zebrafish to Humans

Abstract

Idiopathic Scoliosis (IS), a disease that onsets in adolescence and causes chronic pain, is characterized by three-dimensional spinal curvatures that may require surgery. These curves are more severe in girls than in boys. Zebrafish (Danio rerio) have recently emerged as exemplary models of IS due to their rapid development, externally-developing embryos, and the tractability of CRISPR-Cas9 technology which allows for precise genome editing. Our lab found that defects in motile cilia and resulting deficiencies of cerebrospinal fluid (CSF)-flow cause spinal curves in 3 week-old zebrafish. However, it is unclear which ciliated cells are involved or how the spine normally senses CSF flow to maintain straightness. By analyzing this mechanism, we hope to learn more about how spinal linearity is maintained and the mechanism leading to curvature in IS. Specifically, my work tests the hypothesis that CSF-contacting neurons (CSFcNs) sense CSF flow using ciliary-localized Polycystin proteins (Pkd2l1 and Pkd1l2a). This hypothesis is based on work in other contexts that demonstrate the requirement for Polycystin membrane proteins in flow sensation. I analyzed spine morphology in zebrafish with mutations in pkd2l1 and pkd1l2a genes. I have found spinal curves in pkd2l1 mutants milder than cilia motility mutants. pkd1l2a homozygotes do not exhibit spinal curves in adulthood and decreased viability in pkd1l2a homozygous mutants has prevented robust analysis of IS-like phenotypes. Since motile cilia are present on the surface of several cell types in the brain/spine, I aimed to determine which of these cell types are required for spine straightness by performing cell-specific ablations. Upon removal of neuronal or radial glial subpopulations, I have observed embryonic defects including twitching, early spinal curvature, and paralysis. By conclusion, I hope to improve our knowledge of the role of cilia in scoliosis, which can be applied to refine treatments for those afflicted with IS.