Home LiteratureArticle Details
PMID: 26247711 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes.

eLife ·Vol. 4 ·2015-08-06

Zebrowski DC, Vergarajauregui S, Wu CC, Piatkowski T, Becker R, Leone M, Hirth S, Ricciardi F, Falk N, Giessl A, Just S, Braun T, Weidinger G, Engel FB

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.

Keywords
MTOC cardiomyocyte cardiomyocyte proliferation cell biology centrosome developmental biology heart regeneration mouse newt primary cilium rat stem cells terminal differentiation zebrafish
MeSH Terms
Animals Cell Differentiation Cell Proliferation Centrosome/metabolism Heart/embryology Myocytes, Cardiac/cytology,physiology Rats Salamandridae Zebrafish
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Zebrowski David C
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Vergarajauregui Silvia
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Wu Chi-Chung
Institute for Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
Piatkowski Tanja
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Becker Robert
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Leone Marina
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Hirth Sofia
Department of Medicine II, University of Ulm, Ulm, Germany.
Ricciardi Filomena
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Falk Nathalie
Department of Biology, Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Giessl Andreas
Department of Biology, Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Just Steffen
Department of Medicine II, University of Ulm, Ulm, Germany.
Braun Thomas
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Weidinger Gilbert
Institute for Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.
Engel Felix B
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
References (63)
63 references, click to expand
  1. CDK5RAP2 stimulates microtubule nucleation by the gamma-tubulin ring complex.
    J Cell Biol. 2010 Dec 13;191(6):1089-95 PMID: 21135143
  2. The centrosomal protein pericentrin identified at the basal body complex of the connecting cilium in mouse photoreceptors.
    PLoS One. 2011;6(10):e26496 PMID: 22031837
  3. Restarting life: fertilization and the transition from meiosis to mitosis.
    Nat Rev Mol Cell Biol. 2013 Sep;14(9):549-62 PMID: 23942453
  4. Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.
    Front Oncol. 2013 Nov 12;3:277 PMID: 24282781
  5. Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation.
    Stem Cell Res. 2014 Nov;13(3 Pt B):532-41 PMID: 25306390
  6. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation.
    Nature. 2010 Mar 25;464(7288):606-9 PMID: 20336145
  7. Hamartoma of mature cardiac myocytes: case report and review of the literature.
    Heart Lung Circ. 2011 May;20(5):336-40 PMID: 21354369
  8. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes.
    Genes Dev. 2005 May 15;19(10):1175-87 PMID: 15870258
  9. Aneuploidy: cells losing their balance.
    Genetics. 2008 Jun;179(2):737-46 PMID: 18558649
  10. Parthenogenesis in Xenopus eggs requires centrosomal integrity.
    J Cell Biol. 1990 Feb;110(2):405-15 PMID: 2298811
  11. Nuclei of non-muscle cells bind centrosome proteins upon fusion with differentiating myoblasts.
    PLoS One. 2009;4(12):e8303 PMID: 20011525
  12. The zebra fish cassiopeia mutant reveals that SIL is required for mitotic spindle organization.
    Mol Cell Biol. 2007 Aug;27(16):5887-97 PMID: 17576815
  13. Requirement of a centrosomal activity for cell cycle progression through G1 into S phase.
    Science. 2001 Feb 23;291(5508):1547-50 PMID: 11222860
  14. The Retinoblastoma pathway regulates stem cell proliferation in freshwater planarians.
    Dev Biol. 2013 Jan 15;373(2):442-52 PMID: 23123964
  15. Who needs microtubules? Myogenic reorganization of MTOC, Golgi complex and ER exit sites persists despite lack of normal microtubule tracks.
    PLoS One. 2011;6(12):e29057 PMID: 22216166
  16. Differentiation of cardiac myocytes after mitogen withdrawal exhibits three sequential states of the ventricular growth response.
    J Cell Biol. 1988 Nov;107(5):1911-8 PMID: 3182941
  17. Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest.
    Nat Cell Biol. 2007 Feb;9(2):160-70 PMID: 17330329
  18. Centriolar satellites: busy orbits around the centrosome.
    Eur J Cell Biol. 2011 Dec;90(12):983-9 PMID: 21945726
  19. Centriole maturation requires regulated Plk1 activity during two consecutive cell cycles.
    J Cell Biol. 2014 Sep 29;206(7):855-65 PMID: 25246616
  20. Regulation of cardiomyocyte proliferation during development and regeneration.
    Dev Growth Differ. 2014 Jun;56(5):402-9 PMID: 24738847
  21. Assembling a primary cilium.
    Curr Opin Cell Biol. 2013 Aug;25(4):506-11 PMID: 23747070
  22. Centrin depletion causes cyst formation and other ciliopathy-related phenotypes in zebrafish.
    Cell Cycle. 2011 Nov 15;10(22):3964-72 PMID: 22142866
  23. Q&A: Who needs a centrosome?
    BMC Biol. 2013;11:28 PMID: 23578281
  24. Centrosome loss in the evolution of planarians.
    Science. 2012 Jan 27;335(6067):461-3 PMID: 22223737
  25. Reorganization of microtubule nucleation during muscle differentiation.
    Cell Motil Cytoskeleton. 2005 Jan;60(1):1-13 PMID: 15532031
  26. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy.
    Nat Genet. 2014 Dec;46(12):1283-92 PMID: 25344692
  27. 3D-structured illumination microscopy provides novel insight into architecture of human centrosomes.
    Biol Open. 2012 Oct 15;1(10):965-76 PMID: 23213374
  28. Centriole assembly and the role of Mps1: defensible or dispensable?
    Cell Div. 2011 Apr 14;6:9 PMID: 21492451
  29. Cell cycle regulation in mouse heart during embryonic and postnatal stages.
    Dev Growth Differ. 2012 Oct;54(8):731-8 PMID: 22957921
  30. Generation of noncentrosomal microtubule arrays.
    J Cell Sci. 2006 Oct 15;119(Pt 20):4155-63 PMID: 17038542
  31. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development.
    J Mol Cell Cardiol. 1996 Aug;28(8):1737-46 PMID: 8877783
  32. Cardiomyocyte DNA synthesis and binucleation during murine development.
    Am J Physiol. 1996 Nov;271(5 Pt 2):H2183-9 PMID: 8945939
  33. Anillin localization defect in cardiomyocyte binucleation.
    J Mol Cell Cardiol. 2006 Oct;41(4):601-12 PMID: 16889791
  34. Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4.
    Science. 2015 Jun 5;348(6239):1155-60 PMID: 25931445
  35. Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.
    J Cell Sci. 2007 Dec 15;120(Pt 24):4321-31 PMID: 18042621
  36. A mechanism linking extra centrosomes to chromosomal instability.
    Nature. 2009 Jul 9;460(7252):278-82 PMID: 19506557
  37. Characterization of pericentrin isoforms in vivo.
    Biochem Biophys Res Commun. 2006 Dec 22;351(3):745-9 PMID: 17084386
  38. Transcription of the SCL/TAL1 interrupting Locus (Stil) is required for cell proliferation in adult Zebrafish Retinas.
    J Biol Chem. 2014 Mar 7;289(10):6934-40 PMID: 24469449
  39. Isolation and in vitro culture of primary cardiomyocytes from adult zebrafish hearts.
    Nat Protoc. 2013 Apr;8(4):800-9 PMID: 23538883
  40. Fate of microtubule-organizing centers during myogenesis in vitro.
    J Cell Biol. 1985 Jan;100(1):35-46 PMID: 3880758
  41. Heart regeneration in zebrafish.
    Science. 2002 Dec 13;298(5601):2188-90 PMID: 12481136
  42. The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries.
    Nat Cell Biol. 2011 Oct;13(10):1154-60 PMID: 21968988
  43. Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes.
    J Cell Sci. 2003 Oct 1;116(Pt 19):4001-9 PMID: 12928330
  44. Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle.
    J Cell Biol. 2006 Aug 28;174(5):625-30 PMID: 16943179
  45. The Cep192-organized aurora A-Plk1 cascade is essential for centrosome cycle and bipolar spindle assembly.
    Mol Cell. 2014 Aug 21;55(4):578-91 PMID: 25042804
  46. Chromatin remodelling complex dosage modulates transcription factor function in heart development.
    Nat Commun. 2011;2:187 PMID: 21304516
  47. Assembly of centrosomal proteins and microtubule organization depends on PCM-1.
    J Cell Biol. 2002 Oct 28;159(2):255-66 PMID: 12403812
  48. The conversion of centrioles to centrosomes: essential coupling of duplication with segregation.
    J Cell Biol. 2011 May 16;193(4):727-39 PMID: 21576395
  49. Separase-dependent cleavage of pericentrin B is necessary and sufficient for centriole disengagement during mitosis.
    Cell Cycle. 2012 Jul 1;11(13):2476-85 PMID: 22722493
  50. Cardiac regeneration in model organisms.
    Curr Treat Options Cardiovasc Med. 2014 Mar;16(3):288 PMID: 24496965
  51. Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex.
    Mol Biol Cell. 2002 Sep;13(9):3235-45 PMID: 12221128
  52. Centriole engagement: it's not just cohesin any more.
    Curr Biol. 2013 Aug 5;23(15):R659-60 PMID: 23928085
  53. STIL is required for centriole duplication in human cells.
    J Cell Sci. 2012 Mar 1;125(Pt 5):1353-62 PMID: 22349705
  54. The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin.
    EMBO Rep. 2000 Dec;1(6):524-9 PMID: 11263498
  55. Involvement of a centrosomal protein kendrin in the maintenance of centrosome cohesion by modulating Nek2A kinase activity.
    Biochem Biophys Res Commun. 2010 Jul 23;398(2):217-23 PMID: 20599736
  56. Centriole cycle in Chinese hamster ovary cells as determined by whole-mount electron microscopy.
    J Cell Biol. 1981 Dec;91(3 Pt 1):814-21 PMID: 7328123
  57. Centrosomal localization of cyclins E and A: structural similarities and functional differences.
    Cell Cycle. 2011 Jan 15;10(2):199-205 PMID: 21217199
  58. CDK5RAP2 regulates centriole engagement and cohesion in mice.
    Dev Cell. 2010 Jun 15;18(6):913-26 PMID: 20627074
  59. CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium.
    Hum Mol Genet. 2008 Dec 1;17(23):3796-805 PMID: 18772192
  60. Centrosome control of the cell cycle.
    Trends Cell Biol. 2005 Jun;15(6):303-11 PMID: 15953548
  61. Features of cardiomyocyte proliferation and its potential for cardiac regeneration.
    J Cell Mol Med. 2008 Dec;12(6A):2233-44 PMID: 18662194
  62. The cardiomyocyte cell cycle in hypertrophy, tissue homeostasis, and regeneration.
    Rev Physiol Biochem Pharmacol. 2013;165:67-96 PMID: 23605180
  63. Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression.
    J Cell Biol. 2001 Apr 2;153(1):237-42 PMID: 11285289
Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.05563
Published
2015-08-06
Epub
2015-00-06
Language
English
Region
England
NLM ID
101579614
PMCID
PMC4541494
Subset
IM
External Links
PubMed source DOI: 10.7554/eLife.05563 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2