title: ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.
abstract: The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alla
authors.initials: A
authors.lastname: Aharonov
authors.affiliation: 1] Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2] Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, 40138 Bologna, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
authors.affiliation: Tamman Cardiovascular Research Institute, Leviev Heart Center, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Kain
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yfat
authors.initials: Y
authors.lastname: Yahalom-Ronen
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Weisinger
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Bassat
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Rajchman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Yifa
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Lysenko
authors.affiliation: Tamman Cardiovascular Research Institute, Leviev Heart Center, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Konfino
authors.affiliation: Department of Pediatric Cardiology, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
authors.forename: Julius
authors.initials: J
authors.lastname: Hegesh
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Brenner
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: Tamman Cardiovascular Research Institute, Leviev Heart Center, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leor
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sarig
authors.affiliation: 1] Victor Chang Cardiac Research Institute, Darlinghurst 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia [3] School of Biological and Biomolecular Sciences, University of New South Wales, Kensington 2052, Australia.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eldad
authors.initials: E
authors.lastname: Tzahor
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D054337:Cell Dedifferentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008279:Magnetic Resonance Imaging; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059008:Time-Lapse Imaging; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C524056:Erbb2 protein, mouse; C000605507:Gsk3b protein, mouse
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