PUBLICATION

hace1 influences zebrafish cardiac development via ROS-dependent mechanisms

Authors
Razaghi, B., Steele, S.L., Prykhozhij, S.V., Stoyek, M.R., Hill, J.A., Cooper, M.D., McDonald, L., Lin, W., Daugaard, M., Crapoulet, N., Chacko, S., Lewis, S., Scott, I.C., Sorensen, P.H.B., Berman, J.N.
ID
ZDB-PUB-171013-4
Date
2017
Source
Developmental dynamics : an official publication of the American Association of Anatomists   247(2): 289-303 (Journal)
Registered Authors
Berman, Jason, McDonald, Lindsay, Prykhozhij, Sergey, Razaghi, Babak, Scott, Ian
Keywords
Danio rerio, NADPH oxidases, heart morphology, rac1, reactive oxygen species, tumor suppressor
Datasets
GEO:GSE104380
MeSH Terms
  • Animals
  • Embryo, Nonmammalian
  • Heart/growth & development*
  • Heart Defects, Congenital/etiology
  • NADPH Oxidases
  • Reactive Oxygen Species/metabolism*
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases/physiology*
  • Zebrafish/embryology*
  • rac1 GTP-Binding Protein
PubMed
29024245 Full text @ Dev. Dyn.
Abstract
In this study we reveal a previously undescribed role of the HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) tumor suppressor protein in normal vertebrate heart development using the zebrafish (Danio rerio) model. We examined the link between the cardiac phenotypes associated with hace1 loss of function to the expression of the Rho small family GTPase, rac1, which is a known target of HACE1 and promotes ROS production via its interaction with NADPH oxidase holoenzymes.
We demonstrate that loss of hace1 in zebrafish via morpholino knockdown results in cardiac deformities, specifically a looping defect, where the heart is either tubular or "inverted". Whole mount in situ hybridization of cardiac markers shows distinct abnormalities in ventricular morphology and atrioventricular valve formation in the hearts of these morphants, as well as increased expression of rac1. Importantly, this phenotype appears to be directly related to Nox enzyme-dependent ROS production, as both genetic inhibition by nox1 and nox2 morpholinos or pharmacologic rescue using ROS scavenging agents restore normal cardiac structure.
Our study demonstrates that HACE1 is critical in the normal development and proper function of the heart via a ROS-dependent mechanism. This article is protected by copyright. All rights reserved.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes