Abstract

Adolescent idiopathic scoliosis (AIS) affects 3-4% of children between the ages of 11 and 18. This disorder, characterized by abnormal three-dimensional spinal curvatures that typically develop during periods of rapid growth, occurs in the absence of congenital vertebral malformations or neuromuscular defects. Genetic heterogeneity and a historical lack of appropriate animal models have confounded basic understanding of AIS biology and, as a result, treatment options remain limited. Recently, genetic studies using zebrafish have linked idiopathic-like scoliosis to irregularities in motile cilia-mediated cerebrospinal fluid (CSF) flow. However, since loss of cilia motility in human primary ciliary dyskinesia patients is not fully associated with scoliosis, other pathogenic mechanisms remain to be determined. Here, we demonstrate that zebrafish scospondin (sspo) mutants develop late onset idiopathic-like spinal curvatures in the absence of obvious cilia motility defects. Sspo is a large secreted glycoprotein functionally associated with the subcommissural organ (SCO) and Reissner’s fiber (RF) – ancient and enigmatic organs of the brain ventricular system reported to govern CSF homeostasis, neurogenesis and embryonic axis development. We demonstrate that irregular localization of Sspo around the SCO and RF is associated with acquired idiopathic scoliosis across diverse genetic models. Furthermore Sspo defects are sufficient to induce oxidative stress and neuroinflammatory responses implicated in AIS pathogenesis. Through screening for chemical suppressors of sspo mutant phenotypes, we also identify potent agents capable of blocking severe juvenile spine deformity. Our work thus defines a new useful model for AIS and provides tools to realize novel therapeutic strategies.

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