PUBLICATION

Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations

Authors
Gray, R.S., Wilm, T.P., Smith, J., Bagnat, M., Dale, R.M., Topczewski, J., Johnson, S.L., and Solnica-Krezel, L.
ID
ZDB-PUB-140210-27
Date
2014
Source
Developmental Biology   386(1): 72-85 (Journal)
Registered Authors
Bagnat, Michel, Dale, Rodney M., Gray, Ryan, Johnson, Stephen L., Solnica-Krezel, Lilianna, Topczewski, Jacek, Wilm, Thomas
Keywords
Collagen, Notochord, Osteoblast, Vertebral malformations
MeSH Terms
  • Alleles
  • Animals
  • Collagen Type VIII/genetics
  • Collagen Type VIII/physiology*
  • Crosses, Genetic
  • Gene Expression Regulation, Developmental*
  • In Situ Hybridization
  • Meiosis
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Mutation
  • Notochord/abnormalities
  • Osteoblasts/cytology
  • Osteoblasts/metabolism
  • Protein-Lysine 6-Oxidase/metabolism
  • Spine/abnormalities*
  • Time Factors
  • Zebrafish/embryology*
  • Zebrafish/genetics
PubMed
24333517 Full text @ Dev. Biol.
Abstract

Congenital vertebral malformations (CVM) occur in 1 in 1000 live births and in many cases can cause spinal deformities, such as scoliosis, and result in disability and distress of affected individuals. Many severe forms of the disease, such as spondylocostal dystostosis, are recessive monogenic traits affecting somitogenesis, however the etiologies of the majority of CVM cases remain undetermined. Here we demonstrate that morphological defects of the notochord in zebrafish can generate congenital-type spine defects. We characterize three recessive zebrafish leviathan/col8a1a mutant alleles (m531, vu41, vu105) that disrupt collagen type VIII alpha1a (col8a1a), and cause folding of the embryonic notochord and consequently adult vertebral column malformations. Furthermore, we provide evidence that a transient loss of col8a1a function or inhibition of Lysyl oxidases with drugs during embryogenesis was sufficient to generate vertebral fusions and scoliosis in the adult spine. Using periodic imaging of individual zebrafish, we correlate focal notochord defects of the embryo with vertebral malformations (VM) in the adult. Finally, we show that bends and kinks in the notochord can lead to aberrant apposition of osteoblasts normally confined to well-segmented areas of the developing vertebral bodies. Our results afford a novel mechanism for the formation of VM, independent of defects of somitogenesis, resulting from aberrant bone deposition at regions of misshapen notochord tissue.

Genes / Markers
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes