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. 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.
Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
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DT
Grimes
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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CW
Boswell
Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
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Morante
Mouse Imaging Centre, The Hospital for Sick Children, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada. Department of Medical Biophysics, The University of Toronto, Toronto, Ontario M5G 2M9, Canada.
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RM
Henkelman
Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
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RD
Burdine
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada.
B
B
Ciruna
D000818:Animals; D030801:Animals, Genetically Modified; D002555:Cerebrospinal Fluid / Q000502:physiology*; D002923:Cilia / Q000502:physiology; D004195:Disease Models, Animal; D004805:Ependyma / Q000002:abnormalities; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012600:Scoliosis / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000503:physiopathology*; D013131:Spine / Q000002:abnormalities*; D015027:Zebrafish / Q000002:abnormalities* / Q000134:cerebrospinal fluid / Q000235:genetics; D029961:Zebrafish Proteins
D029961:Zebrafish Proteins; D020794:Receptor Protein-Tyrosine Kinases; C581480:ptk7b protein, zebrafish