PUBLICATION
SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis
- Authors
- 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.
- ID
- ZDB-PUB-200511-1
- 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
-
- Cerebral Ventricles/metabolism*
- Disease Models, Animal
- Humans
- Cell Adhesion Molecules, Neuronal/genetics*
- Cell Adhesion Molecules, Neuronal/metabolism
- Morphogenesis*
- Inflammation/physiopathology*
- Spine/abnormalities
- Spine/growth & development*
- Animals
- Zebrafish/abnormalities*
- Zebrafish/growth & development
- Spinal Cord/abnormalities
- Spinal Cord/growth & development
- Spinal Cord/immunology*
- PubMed
- 32386528 Full text @ Curr. Biol.
Citation
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. (2020) SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis. Current biology : CB. 30(12):2363-2373.e6.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping