title: Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge.
abstract: The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration. In both cases proliferation is finally arrested. We show that in neurofibroma, the induction of Jmjd3 (jumonji domain containing 3, histone lysine demethylase) removes trimethyl groups on lysine-27 of histone-H3 and epigenetically activates the Ink4a/Arf-locus, forcing Schwann cells towards replicative senescence. Remarkably, blocking this mechanism allows unrestricted proliferation, inducing malignant transformation of neurofibromas. Interestingly, our data suggest that in injured nerves, Schwann cells epigenetically activate the same locus to switch off proliferation and enter the senescence programme. Indeed, when this pathway is genetically blocked, Schwann cells fail to drop out of the cell cycle and continue to proliferate. We postulate that the Ink4a/Arf-locus is expressed as part of a physiological response that prevents uncontrolled proliferation of the de-differentiated Schwann cell generated during nerve regeneration, a response that is also activated to avoid overproliferation after tumorigenic stimuli in the peripheral nervous system.
authors.affiliation: Instituto de Neurociencias de Alicante UMH-CSIC, San Juan de Alicante 03550, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Gomez-Sanchez
authors.forename: Clara
authors.initials: C
authors.lastname: Gomis-Coloma
authors.forename: Cruz
authors.initials: C
authors.lastname: Morenilla-Palao
authors.forename: Gloria
authors.initials: G
authors.lastname: Peiro
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Hugo
authors.initials: H
authors.lastname: Cabedo
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D057890:Epigenomics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics; D009455:Neurofibroma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012583:Schwann Cells / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D014855:Wallerian Degeneration / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D006657:Histones; D019394:Ki-67 Antigen; C094131:NRG1 protein, human; D020890:Neuregulin-1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse
keywords: Schwann cells; cellular biology; nerve injury; nerve regeneration; neuroscience