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

Ryan S. Gray*, Thomas P. Wilm, Jeff Smith, Michel Bagnat, Rodney M. Dale, Jacek Topczewski, Stephen L. Johnson, Lilianna Solnica-Krezel

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)72-85
Number of pages14
JournalDevelopmental Biology
Volume386
Issue number1
DOIs
StatePublished - Feb 1 2014

Keywords

  • Collagen
  • Notochord
  • Osteoblast
  • Vertebral malformations

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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    Gray, R. S., Wilm, T. P., Smith, J., Bagnat, M., Dale, R. M., Topczewski, J., Johnson, S. L., & Solnica-Krezel, L. (2014). Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations. Developmental Biology, 386(1), 72-85. https://doi.org/10.1016/j.ydbio.2013.11.028