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
  • Inflammation/physiopathology*
  • Morphogenesis*
  • Cell Adhesion Molecules, Neuronal/genetics*
  • Cell Adhesion Molecules, Neuronal/metabolism
  • Spine/abnormalities
  • Spine/growth & development*
  • Spinal Cord/abnormalities
  • Spinal Cord/growth & development
  • Spinal Cord/immunology*
  • Animals
  • Disease Models, Animal
  • Zebrafish/abnormalities*
  • Zebrafish/growth & development
  • Humans
  • Cerebral Ventricles/metabolism*
(all 15)
PubMed
32386528 Full text @ Curr. Biol.
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
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
dmh4
    Point Mutation
    gl22TgTransgenic Insertion
      gl23TgTransgenic Insertion
        hsc9
          Small Deletion
          hsc105
            Insertion
            hsc106
              Small Deletion
              hsc107
                Small Deletion
                hsc108
                  Small Deletion
                  i114TgTransgenic Insertion
                    teg15a
                      Point Mutation
                      1 - 10 of 12
                      Show
                      Human Disease / Model
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      sspoCRISPR3-sspoCRISPR
                      sspoCRISPR4-sspoCRISPR
                      1 - 2 of 2
                      Show
                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-RFpolyclonal
                        Rabbit
                        Ab1-tub-glutmonoclonal
                          Mouse
                          1 - 2 of 2
                          Show
                          Orthology
                          No data available
                          Engineered Foreign Genes
                          Marker Marker Type Name
                          EGFPEFGEGFP
                          GFPEFGGFP
                          mCherryEFGmCherry
                          1 - 3 of 3
                          Show
                          Mapping
                          No data available