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ZIRC
ZFIN ID: ZDB-PUB-171013-4
hace1 influences zebrafish cardiac development via ROS-dependent mechanisms
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.
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
Microarrays: 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.
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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.
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