Establishing Zebrafish Cilia Motility Mutants as Models of Human Idiopathic Scoliosis

Abstract

Scoliosis is a musculoskeletal deformity characterized by spinal curves of 10° or more. While congenital scoliosis results from malformations present at birth, idiopathic scoliosis often develops during adolescence. A previously unidentified zebrafish cilia motility mutant, zoolander (zoo), was shown to develop scoliotic curves in juveniles. zoo was found to possess a nonsense mutation in dyslexia susceptibility 1 candidate gene 1, a gene previously implicated in cilia motility. Scoliosis onset in zoo was consistent with that of other cilia motility mutants, which prompted an investigation of zebrafish cilia motility mutants as potential animal models of human scoliosis. A close examination of curve onset in zoo and kurly, a cilia motility mutant in c21orf59, demonstrated that scoliosis is not associated with congenital defects. This supports the establishment of zebrafish cilia motility mutants as models of idiopathic scoliosis. Preliminary characterization of spinal morphology in zoo revealed that scoliotic mutants present abnormal musculature and potential defects in cell proliferation. Future studies should seek to contextualize these findings as causes or consequences of scoliosis, and thereby explore the mechanism through which compromised cilia motility results in scoliosis onset. Currently, our primary hypothesis is that the generation of cerebrospinal fluid flow by ependymal cilia in the spinal canal is essential for maintaining a straight backbone throughout life.