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
(all 10)
PubMed
29024245 Full text @ Dev. Dyn.
Abstract
Background 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.
Results 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.
Conclusions 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
Marker Marker Type Name
blfGENEbloody fingers
bmp4GENEbone morphogenetic protein 4
bmp7aGENEbone morphogenetic protein 7a
cybbGENEcytochrome b-245, beta polypeptide (chronic granulomatous disease)
hace1GENEHECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
has2GENEhyaluronan synthase 2
lmnaGENElamin A
mitfaGENEmelanocyte inducing transcription factor a
mpv17GENEmitochondrial inner membrane protein MPV17
myh6GENEmyosin, heavy chain 6, cardiac muscle, alpha
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Figures
Figure Gallery (5 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
AB + MO1-hace1standard conditionsLong-pec
mitfaw2/w2; mpv17a9/a9 + MO1-hace1standard conditionsLong-pec
sd21Tgstandard conditionsLong-pec
sd21Tgstandard conditionsLong-pec
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    sd21TgTransgenic Insertion
      twu34TgTransgenic Insertion
        w2
          		Point Mutation
          y1TgTransgenic Insertion
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            cybbMO2-cybbMRPHLNO
            hace1MO1-hace1MRPHLNO
            nox1MO1-nox1MRPHLNO
            rac1aMO1-rac1aMRPHLNO
            1 - 4 of 4
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            Fish
            Fish
            AB
            AB + MO1-hace1
            mitfaw2/w2; mpv17a9/a9
            mitfaw2/w2; mpv17a9/a9 + MO1-hace1
            sd21Tg
            sd21Tg + MO1-hace1
            sd21Tg + MO1-hace1 + MO1-nox1 + MO2-cybb
            sd21Tg + MO1-nox1
            sd21Tg + MO1-nox1 + MO2-cybb
            sd21Tg + MO2-cybb
            1 - 10 of 12
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            Antibodies
            Orthology
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            mCherryEFGmCherry
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            Mapping
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            Citation
            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. (2017) hace1 influences zebrafish cardiac development via ROS-dependent mechanisms. Developmental Dynamics : an official publication of the American Association of Anatomists. 247(2):289-303.