title: Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations.
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.
authors: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: grayr@wustl.edu.
authors: Ryan S
authors: RS
authors: Gray
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Thomas P
authors: TP
authors: Wilm
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Jeff
authors: J
authors: Smith
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Michel
authors: M
authors: Bagnat
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Rodney M
authors: RM
authors: Dale
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Jacek
authors: J
authors: Topczewski
authors: Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors: Stephen L
authors: SL
authors: Johnson
authors: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Lilianna
authors: L
authors: Solnica-Krezel
mesh_terms: D000483:Alleles; D000818:Animals; D024102:Collagen Type VIII / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008540:Meiosis; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009672:Notochord / Q000002:abnormalities; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D013131:Spine / Q000002:abnormalities*; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: D024102:Collagen Type VIII; C587104:col8a1a, zebrafish; D008249:Protein-Lysine 6-Oxidase
keywords: Collagen; Notochord; Osteoblast; Vertebral malformations