Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines

Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and eventual death in 3–5 years after the disease onset. More than 50 mutations linked to ALS have been found in the g...

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Main Authors: Alexandra Lissouba, Meijiang Liao, Edor Kabashi, Pierre Drapeau
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-12-01
Series:Frontiers in Molecular Neuroscience
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fnmol.2018.00463/full
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author Alexandra Lissouba
Meijiang Liao
Edor Kabashi
Edor Kabashi
Pierre Drapeau
author_facet Alexandra Lissouba
Meijiang Liao
Edor Kabashi
Edor Kabashi
Pierre Drapeau
author_sort Alexandra Lissouba
collection DOAJ
description Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and eventual death in 3–5 years after the disease onset. More than 50 mutations linked to ALS have been found in the gene TARDBP, encoding the protein TDP-43 that is the predominant component of neuronal inclusions in ALS. TDP-43 is an RNA binding protein with glycine-rich domains that binds to more than 6,000 RNAs in the human brain. However, ALS-related mutations do not appear to affect the function of these genes, indicating that a toxic gain-of-function may occur. We generated transgenic zebrafish lines expressing human TDP-43, either the wild-type form or the ALS-causative G348C mutation identified in a subset of ALS patients, with the transgene expression driven by an inducible heat shock promoter in order to bypass a potential early mortality. The expression of the mutant but not the wild-type human TDP-43 in zebrafish embryos induced a reduction of the locomotor activity in response to touch compared to controls and moderate axonopathy of the motor neurons of the spinal cord, with premature branching of the main axonal branch, recapitulating previous results obtained by mRNA injections. We used these lines to investigate transcriptomic changes due to the presence of mutant TDP-43 using RNA sequencing and have found 159 genes that are differentially expressed compared to control, with 67 genes up-regulated and 92 genes down-regulated. These transcriptomic changes are in line with recent transcriptomic data obtained in mouse models, indicating that these zebrafish transgenic lines are adequate to further study TDP-43-related ALS.
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spelling doaj.art-2c7fd92a609349c19caf30418a03928f2022-12-22T00:03:34ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-12-011110.3389/fnmol.2018.00463426680Transcriptomic Analysis of Zebrafish TDP-43 Transgenic LinesAlexandra Lissouba0Meijiang Liao1Edor Kabashi2Edor Kabashi3Pierre Drapeau4Department of Pathology and Cell Biology and Research Center of the University of Montréal Hospital Center, University of Montreal, Montréal, QC, CanadaDepartment of Pathology and Cell Biology and Research Center of the University of Montréal Hospital Center, University of Montreal, Montréal, QC, CanadaUMR CNRS 1127, UPMC INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Sorbonne Université Paris VI, Paris, FranceInstitut Imagine, UMR INSERM 1163, Hospital Necker-Enfants, Université Paris Descartes, Paris, FranceDepartment of Pathology and Cell Biology and Research Center of the University of Montréal Hospital Center, University of Montreal, Montréal, QC, CanadaAmyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and eventual death in 3–5 years after the disease onset. More than 50 mutations linked to ALS have been found in the gene TARDBP, encoding the protein TDP-43 that is the predominant component of neuronal inclusions in ALS. TDP-43 is an RNA binding protein with glycine-rich domains that binds to more than 6,000 RNAs in the human brain. However, ALS-related mutations do not appear to affect the function of these genes, indicating that a toxic gain-of-function may occur. We generated transgenic zebrafish lines expressing human TDP-43, either the wild-type form or the ALS-causative G348C mutation identified in a subset of ALS patients, with the transgene expression driven by an inducible heat shock promoter in order to bypass a potential early mortality. The expression of the mutant but not the wild-type human TDP-43 in zebrafish embryos induced a reduction of the locomotor activity in response to touch compared to controls and moderate axonopathy of the motor neurons of the spinal cord, with premature branching of the main axonal branch, recapitulating previous results obtained by mRNA injections. We used these lines to investigate transcriptomic changes due to the presence of mutant TDP-43 using RNA sequencing and have found 159 genes that are differentially expressed compared to control, with 67 genes up-regulated and 92 genes down-regulated. These transcriptomic changes are in line with recent transcriptomic data obtained in mouse models, indicating that these zebrafish transgenic lines are adequate to further study TDP-43-related ALS.https://www.frontiersin.org/article/10.3389/fnmol.2018.00463/fullamyotrophic lateral sclerosisALSzebrafishTDP-43TARDBP
spellingShingle Alexandra Lissouba
Meijiang Liao
Edor Kabashi
Edor Kabashi
Pierre Drapeau
Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
Frontiers in Molecular Neuroscience
amyotrophic lateral sclerosis
ALS
zebrafish
TDP-43
TARDBP
title Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
title_full Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
title_fullStr Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
title_full_unstemmed Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
title_short Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines
title_sort transcriptomic analysis of zebrafish tdp 43 transgenic lines
topic amyotrophic lateral sclerosis
ALS
zebrafish
TDP-43
TARDBP
url https://www.frontiersin.org/article/10.3389/fnmol.2018.00463/full
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AT edorkabashi transcriptomicanalysisofzebrafishtdp43transgeniclines
AT pierredrapeau transcriptomicanalysisofzebrafishtdp43transgeniclines