ZFIN ID: ZDB-PUB-200511-1
SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis
Rose, C.D., Pompili, D., Henke, K., Van Gennip, J.L.M., Meyer-Miner, A., Rana, R., Gobron, S., Harris, M.P., Nitz, M., Ciruna, B.
Date: 2020
Source: Current biology : CB   30(12): 2363-2373.e6 (Journal)
Registered Authors: Ciruna, Brian, Harris, Matthew, Henke, Katrin
Keywords: N-acetyl-L-cysteine ethyl ester, Reissner’s fiber, SCO-spondin, adolescent idiopathic scoliosis, cerebrospinal fluid, cyclooxygenase inhibitor, neuroinflammation, oxidative stress, subcommissural organ, zebrafish
MeSH Terms:
  • Animals
  • Cell Adhesion Molecules, Neuronal/genetics*
  • Cell Adhesion Molecules, Neuronal/metabolism
  • Cerebral Ventricles/metabolism*
  • Disease Models, Animal
  • Humans
  • Inflammation/physiopathology*
  • Morphogenesis*
  • Spinal Cord/abnormalities
  • Spinal Cord/growth & development
  • Spinal Cord/immunology*
  • Spine/abnormalities
  • Spine/growth & development*
  • Zebrafish/abnormalities*
  • Zebrafish/growth & development
PubMed: 32386528 Full text @ Curr. Biol.
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.