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Dev Biol. 2014 Feb 1;386(1):72-85. doi: 10.1016/j.ydbio.2013.11.028. Epub 2013 Dec 11.

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

Author information

1
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: grayr@wustl.edu.
2
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
4
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
5
Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
6
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

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.

KEYWORDS:

Collagen; Notochord; Osteoblast; Vertebral malformations

PMID:
24333517
PMCID:
PMC3938106
DOI:
10.1016/j.ydbio.2013.11.028
[Indexed for MEDLINE]
Free PMC Article

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