title: Dicer in Schwann cells is required for myelination and axonal integrity.
abstract: Dicer is responsible for the generation of mature micro-RNAs (miRNAs) and loading them into RNA-induced silencing complex (RISC). RISC functions as a probe that targets mRNAs leading to translational suppression and mRNA degradation. Schwann cells (SCs) in the peripheral nervous system undergo remarkable differentiation both in morphology and gene expression patterns throughout lineage progression to myelinating and nonmyelinating phenotypes. Gene expression in SCs is particularly tightly regulated and critical for the organism, as highlighted by the fact that a 50% decrease or an increase to 150% of normal gene expression of some myelin proteins, like PMP22, results in peripheral neuropathies. Here, we selectively deleted Dicer and consequently gene expression regulation by mature miRNAs from Mus musculus SCs. Our results show that in the absence of Dicer, most SCs arrest at the promyelinating stage and fail to start forming myelin. At the molecular level, the promyelinating transcription factor Krox20 and several myelin proteins [including myelin associated glycoprotein (MAG) and PMP22] were strongly reduced in mutant sciatic nerves. In contrast, the myelination inhibitors SOX2, Notch1, and Hes1 were increased, providing an additional potential basis for impaired myelination. A minor fraction of SCs, with some peculiar differences between sensory and motor fibers, overcame the myelination block and formed unusually thin myelin, in line with observed impaired neuregulin and AKT signaling. Surprisingly, we also found signs of axonal degeneration in Dicer mutant mice. Thus, our data indicate that miRNAs critically regulate Schwann cell gene expression that is required for myelination and to maintain axons via axon-glia interactions.
authors.affiliation: Institute of Cell Biology, Department of Biology, Eidgenössische Technische Hochschule (ETH) Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.forename: Reto
authors.initials: R
authors.lastname: Baumann
authors.forename: Camilla
authors.initials: C
authors.lastname: Norrmén
authors.forename: Christian
authors.initials: C
authors.lastname: Somandin
authors.forename: Michaela
authors.initials: M
authors.lastname: Miehe
authors.forename: Claire
authors.initials: C
authors.lastname: Jacob
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.forename: Heike
authors.initials: H
authors.lastname: Hall-Bozic
authors.forename: Ned
authors.initials: N
authors.lastname: Mantei
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D043244:Ribonuclease III; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000502:physiology / Q000648:ultrastructure; D013126:Spinal Nerve Roots / Q000502:physiology / Q000648:ultrastructure; D000072056:Transcription Factor HES-1; D014741:Video Recording
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053487:DEAD-box RNA Helicases; D051767:Early Growth Response Protein 2; D004722:Endoribonucleases; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009185:Myelin Proteins; D051881:Receptor, Notch1; D043244:Ribonuclease III; D055748:SOXB1 Transcription Factors; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C527783:Sox2 protein, mouse; C509781:Dicer1 protein, mouse
references.citation: J Neurosci. 2008 Apr 23;28(17):4322-30
references.pmid: 18434510
references.citation: Annu Rev Neurosci. 2008;31:535-61
references.pmid: 18558866
references.citation: Microsc Res Tech. 1998 Jun 1;41(5):372-8
references.pmid: 9672420
references.citation: Cold Spring Harb Symp Quant Biol. 2006;71:551-64
references.pmid: 17381339
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):23-36
references.pmid: 17183358
references.citation: Mol Cell Endocrinol. 2010 Feb 5;315(1-2):63-73
references.pmid: 19799966
references.citation: Mol Reprod Dev. 2009 Jul;76(7):678-88
references.pmid: 19197916
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: PLoS One. 2007 Dec 26;2(12):e1331
references.pmid: 18159229
references.citation: J Neurosci. 2008 Mar 19;28(12):2959-64
references.pmid: 18353998
references.citation: J Neurosci. 2004 Jul 28;24(30):6724-32
references.pmid: 15282275
references.citation: Brain Res. 1994 Jun 13;648(1):162-6
references.pmid: 7522923
references.citation: Neuron. 2001 May;30(2):355-68
references.pmid: 11394999
references.citation: Diabetes. 2007 Dec;56(12):2938-45
references.pmid: 17804764
references.citation: Dev Biol. 2009 Apr 15;328(2):328-41
references.pmid: 19389351
references.citation: Nat Rev Mol Cell Biol. 2009 Feb;10(2):126-39
references.pmid: 19165215
references.citation: Glia. 2008 Nov 1;56(14):1578-89
references.pmid: 18803325
references.citation: Brain. 1999 Aug;122 ( Pt 8):1563-77
references.pmid: 10430839
references.citation: Science. 2008 Mar 28;319(5871):1787-9
references.pmid: 18369136
references.citation: Glia. 2008 Nov 1;56(14):1541-51
references.pmid: 18803322
references.citation: Nucleic Acids Res. 2003 Sep 15;31(18):5405-12
references.pmid: 12954777
references.citation: J Neurosci. 2008 May 7;28(19):4878-87
references.pmid: 18463241
references.citation: EMBO Rep. 2006 Jan;7(1):52-8
references.pmid: 16311519
references.citation: J Cell Biol. 2008 May 19;181(4):625-37
references.pmid: 18490512
references.citation: Genes Dev. 1998 Jun 15;12(12):1825-36
references.pmid: 9637684
references.citation: Curr Opin Neurobiol. 2006 Oct;16(5):492-500
references.pmid: 16962312
references.citation: J Neurosci Res. 1999 Aug 1;57(3):332-41
references.pmid: 10412024
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2596-601
references.pmid: 15695336
references.citation: Brain Res. 1986 May 14;373(1-2):288-302
references.pmid: 3719313
references.citation: J Am Soc Nephrol. 2008 Nov;19(11):2069-75
references.pmid: 18832437
references.citation: J Peripher Nerv Syst. 2005 Jun;10(2):128-43
references.pmid: 15958125
references.citation: Nat Rev Neurosci. 2003 Sep;4(9):714-26
references.pmid: 12951564
references.citation: Nat Rev Neurosci. 2005 Sep;6(9):671-82
references.pmid: 16136171
references.citation: Nature. 1994 Oct 27;371(6500):796-9
references.pmid: 7935840
references.citation: J Neurosci. 2000 Jun 15;20(12):4635-45
references.pmid: 10844033
references.citation: Glia. 2008 Nov 1;56(14):1518-31
references.pmid: 18803315
references.citation: J Peripher Nerv Syst. 2008 Jun;13(2):122-35
references.pmid: 18601657
references.citation: J Pathol. 2009 Nov;219(3):365-72
references.pmid: 19718708
references.citation: Nature. 2003 Sep 25;425(6956):415-9
references.pmid: 14508493
references.citation: Development. 2004 Nov;131(22):5599-612
references.pmid: 15496445
references.citation: Science. 2004 Apr 30;304(5671):700-3
references.pmid: 15044753
references.citation: Nat Neurosci. 2006 Dec;9(12):1520-5
references.pmid: 17099708
references.citation: Anat Rec. 1986 May;215(1):71-81
references.pmid: 3706794
references.citation: J Cell Biol. 2009 Apr 6;185(1):147-61
references.pmid: 19349584
references.citation: Glia. 2009 Oct;57(13):1450-7
references.pmid: 19243017
references.citation: Nat Neurosci. 2009 Jul;12(7):839-47
references.pmid: 19525946
references.citation: Glia. 2008 Nov 1;56(14):1481-90
references.pmid: 18803317
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2111-6
references.pmid: 18256189
references.citation: Nat Genet. 2003 Nov;35(3):215-7
references.pmid: 14528307
references.citation: Curr Opin Neurobiol. 1993 Oct;3(5):805-9
references.pmid: 8260833
references.citation: Nat Neurosci. 2004 Sep;7(9):930-8
references.pmid: 15322547