SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis

• Published in: Current biology Vol. 30; no. 12; pp. 2363 - 2373.e6
• Main Authors: Rose, Chloe D., Pompili, David, Henke, Katrin, Van Gennip, Jenica L.M., Meyer-Miner, Anne, Rana, Rahul, Gobron, Stéphane, Harris, Matthew P., Nitz, Mark, Ciruna, Brian
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 22.06.2020
• Subjects: adolescent idiopathic scoliosis; cerebrospinal fluid; cyclooxygenase inhibitor; N-acetyl-L-cysteine ethyl ester; neuroinflammation; oxidative stress; Reissner’s fiber; SCO-spondin; subcommissural organ; zebrafish; subcommissural organ; N-acetyl-L-cysteine ethyl ester; SCO-spondin; neuroinflammation; cerebrospinal fluid; cyclooxygenase inhibitor; Reissner’s fiber; zebrafish; oxidative stress; adolescent idiopathic scoliosis
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.04.020

Adolescent idiopathic scoliosis (AIS) affects 3% to 4% of children between the ages of 11 and 18 [1, 2]. 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 [1]. Genetic heterogeneity [3] and a historical lack of appropriate animal models [4] have confounded basic understanding of AIS biology; thus, treatment options remain limited [5, 6]. Recently, genetic studies using zebrafish have linked idiopathic-like scoliosis to irregularities in motile cilia-mediated cerebrospinal fluid flow [7–9]. However, because loss of cilia motility in human primary ciliary dyskinesia patients is not fully associated with scoliosis [10, 11], 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 and Reissner’s fiber [12]—ancient and enigmatic organs of the brain ventricular system reported to govern cerebrospinal fluid homeostasis [13, 14], neurogenesis [12, 15–18], and embryonic morphogenesis [19]. We demonstrate that irregular deposition of Sspo within brain ventricles is associated with idiopathic-like scoliosis across diverse genetic models. Furthermore, Sspo defects are sufficient to induce oxidative stress and neuroinflammatory responses implicated in AIS pathogenesis [9]. 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 preclinical model of AIS and provides tools to realize novel therapeutic strategies. •SCO-spondin and Reissner’s fiber defects cause idiopathic scoliosis (IS) in zebrafish•Neuroinflammation, downstream of abnormal CSF homeostasis, drives spinal curvature•Embryonic axial defects are molecularly and functionally linked to juvenile-onset IS•Chemical suppressor screens identify potent agents that block severe IS progression Rose et al. describe a new zebrafish model of idiopathic-like scoliosis, implicate ancient and enigmatic brain organ systems in spine development, identify neuroimmune responses as a driving force behind spinal curve progression, and develop a chemical suppressor screen paradigm that may translate to novel therapeutic strategies.