title: Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes.
abstract: Mammalian cardiomyocytes become post-mitotic shortly after birth. Understanding how this occurs is highly relevant to cardiac regenerative therapy. Yet, how cardiomyocytes achieve and maintain a post-mitotic state is unknown. Here, we show that cardiomyocyte centrosome integrity is lost shortly after birth. This is coupled with relocalization of various centrosome proteins to the nuclear envelope. Consequently, postnatal cardiomyocytes are unable to undergo ciliogenesis and the nuclear envelope adopts the function as cellular microtubule organizing center. Loss of centrosome integrity is associated with, and can promote, cardiomyocyte G0/G1 cell cycle arrest suggesting that centrosome disassembly is developmentally utilized to achieve the post-mitotic state in mammalian cardiomyocytes. Adult cardiomyocytes of zebrafish and newt, which are able to proliferate, maintain centrosome integrity. Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart.
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: David C
authors.initials: DC
authors.lastname: Zebrowski
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vergarajauregui
authors.affiliation: Institute for Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Piatkowski
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Becker
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Leone
authors.affiliation: Department of Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hirth
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Filomena
authors.initials: F
authors.lastname: Ricciardi
authors.affiliation: Department of Biology, Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Falk
authors.affiliation: Department of Biology, Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Giessl
authors.affiliation: Department of Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Institute for Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Weidinger
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Engel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism*; D006321:Heart / Q000196:embryology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D051381:Rats; D012455:Salamandridae; D015027:Zebrafish
keywords: MTOC; cardiomyocyte; cardiomyocyte proliferation; cell biology; centrosome; developmental biology; heart regeneration; mouse; newt; primary cilium; rat; stem cells; terminal differentiation; zebrafish