title: A neural crest origin for cohesinopathy heart defects.
abstract: Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency and can reach up to 30% in CdLS. The mechanisms by which heart defects occur are enigmatic, but assumed to be developmental in origin. In this study, we depleted cohesin subunit Rad21 by 70-80% in a zebrafish cohesinopathy model. The hearts of Rad21-depleted animals were smaller, often failed to loop, and functioned less efficiently than size-matched controls. Functional deficiency was accompanied by valve defects and reduced ejection fraction. Interestingly, neural crest cells failed to populate the heart and instead exhibited a wandering behavior. Consequently, these cells also failed to condense correctly into pharyngeal arches. Transcriptome analysis revealed that Wnt pathway, chemokine and cadherin genes are dysregulated at the time of cardiac neural crest development. Our results give insight into the etiology of heart defects in the cohesinopathies, and raise the possibility that mild mutations in cohesin genes may be causative of a fraction of congenital heart disease in human populations.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schuster
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and.
authors.forename: Bryony
authors.initials: B
authors.lastname: Leeke
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and.
authors.forename: Michael
authors.initials: M
authors.lastname: Meier
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and.
authors.forename: Trent
authors.initials: T
authors.lastname: Newman
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Burgess
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, PO Box 913, Dunedin, New Zealand and julia.horsfield@otago.ac.nz.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Horsfield
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics*; D002465:Cell Movement; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000473:pathology; D006351:Heart Valves / Q000002:abnormalities; D009432:Neural Crest / Q000002:abnormalities*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D029961:Zebrafish Proteins; D000097722:Cohesins; C000598009:rad21a protein, zebrafish