ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

Madeline Hayes, Xiaochong Gao, Lisa X Yu, Nandina Paria, R. Mark Henkelman, Carol A. Wise and Brian Ciruna ()
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Madeline Hayes: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children
Xiaochong Gao: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
Lisa X Yu: Mouse Imaging Centre (MICe), The Hospital for Sick Children
Nandina Paria: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
R. Mark Henkelman: Mouse Imaging Centre (MICe), The Hospital for Sick Children
Carol A. Wise: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
Brian Ciruna: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease.

Date: 2014
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DOI: 10.1038/ncomms5777

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