Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature

Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the mechanisms underlying this spinal deformity remain unknown. Here we show that ptk7 mutant zebrafish, a faithful developmental model of IS, exhibit defects in ependymal cell cilia development and cerebrospinal fluid (CSF) flow. Trans...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2016-06, Vol.352 (6291), p.1341-1344
Main Authors: Grimes, D. T., Boswell, C. W., Morante, N. F. C., Henkelman, R. M., Burdine, R. D., Ciruna, B.
Format: Article
Language:English
Subjects:
Anatomy
Animals
Animals, Genetically Modified
Cerebrospinal fluid
Cerebrospinal Fluid - physiology
Children
Children & youth
Cilia - physiology
Curved
Danio rerio
Defects
Disease Models, Animal
Ependyma - abnormalities
Fish
Hydrocephalus - genetics
Hydrocephalus - pathology
Mathematical analysis
Mutation
Receptor Protein-Tyrosine Kinases - genetics
Scoliosis
Scoliosis - cerebrospinal fluid
Scoliosis - genetics
Scoliosis - physiopathology
Spine
Spine - abnormalities
Three dimensional
Zebrafish
Zebrafish - abnormalities
Zebrafish - cerebrospinal fluid
Zebrafish - genetics
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Summary:Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the mechanisms underlying this spinal deformity remain unknown. Here we show that ptk7 mutant zebrafish, a faithful developmental model of IS, exhibit defects in ependymal cell cilia development and cerebrospinal fluid (CSF) flow. Transgenic reintroduction of Ptk7 in motile ciliated lineages prevents scoliosis in ptk7 mutants, and mutation of multiple independent cilia motility genes yields IS phenotypes. We define a finite developmental window for motile cilia in zebrafish spine morphogenesis. Notably, restoration of cilia motility after the onset of scoliosis blocks spinal curve progression. Together, our results indicate a critical role for cilia-driven CSF flow in spine development, implicate irregularities in CSF flow as an underlying biological cause of IS, and suggest that noninvasive therapeutic intervention may prevent severe scoliosis.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaf6419