PUBLICATION
A neural crest origin for cohesinopathy heart defects
- Authors
- Schuster, K., Leeke, B., Meier, M., Wang, Y., Newman, T., Burgess, S., Horsfield, J.A.
- ID
- ZDB-PUB-151001-6
- Date
- 2015
- Source
- Human molecular genetics 24(24): 7005-16 (Journal)
- Registered Authors
- Horsfield, Jules
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Cycle Proteins/deficiency
- Cell Cycle Proteins/genetics*
- Cell Movement
- Chromosomal Proteins, Non-Histone/genetics
- Disease Models, Animal
- Gene Deletion
- Gene Expression Regulation, Developmental
- Heart Defects, Congenital/embryology*
- Heart Defects, Congenital/genetics
- Heart Defects, Congenital/pathology
- Heart Valves/abnormalities
- Neural Crest/abnormalities*
- Zebrafish
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics*
- PubMed
- 26420840 Full text @ Hum. Mol. Genet.
Citation
Schuster, K., Leeke, B., Meier, M., Wang, Y., Newman, T., Burgess, S., Horsfield, J.A. (2015) A neural crest origin for cohesinopathy heart defects. Human molecular genetics. 24(24):7005-16.
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 characterised 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping