title: M2 muscarinic receptor activation regulates Schwann cell differentiation and myelin organization.
abstract: Glial cells express acetylcholine receptors. In particular, rat Schwann cells express different muscarinic receptor subtypes, the most abundant of which is the M2 subtype. M2 receptor activation causes a reversible arrest of the cell cycle. This negative effect on Schwann cell proliferation suggests that these cells may possibly progress into a differentiating program. In this study we analyzed the in vitro modulation, by the M2 agonist arecaidine, of transcription factors and specific signaling pathways involved in Schwann cell differentiation. The arecaidine-induced M2 receptor activation significantly upregulates transcription factors involved in the promyelinating phase (e.g., Sox10 and Krox20) and downregulates proteins involved in the maintenance of the undifferentiated state (e.g., c-jun, Notch-1, and Jagged-1). Furthermore, arecaidine stimulation significantly increases the expression of myelin proteins, which is accompanied by evident changes in cell morphology, as indicated by electron microscopy analysis, and by substantial cellular re-distribution of actin and cell adhesion molecules. Moreover, ultrastructural and morphometric analyses on sciatic nerves of M2/M4 knockout mice show numerous degenerating axons and clear alterations in myelin organization compared with wild-type mice. Therefore, our data demonstrate that acetylcholine mediates axon-glia cross talk, favoring Schwann cell progression into a differentiated myelinating phenotype and contributing to compact myelin organization.
authors.affiliation: Dipartmento di Biologia e Biotecnologie "Charles Darwin,", "Sapienza" Università di Roma, Roma, Italy; Centro di ricerca in Neurobiologia "Daniel Bovet,", "Sapienza" Università di Roma, Roma, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Uggenti
authors.forename: M Egle
authors.initials: ME
authors.lastname: De Stefano
authors.forename: Michele
authors.initials: M
authors.lastname: Costantino
authors.forename: Simona
authors.initials: S
authors.lastname: Loreti
authors.forename: Annalinda
authors.initials: A
authors.lastname: Pisano
authors.forename: Bice
authors.initials: B
authors.lastname: Avallone
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
authors.forename: Valerio
authors.initials: V
authors.lastname: Magnaghi
authors.forename: Ada Maria
authors.initials: AM
authors.lastname: Tata
mesh_terms: D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D055495:Neurogenesis / Q000187:drug effects; D018373:Peripheral Nervous System Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D018373:Peripheral Nervous System Agents; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D014157:Transcription Factors; C015688:arecaidine; D001115:Arecoline
keywords: Schwann cells; acetylcholine; muscarinic receptors; myelin proteins; transcription factors