Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination.
The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer(-/-) Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism.
Bremer
Juliane
J
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
O'Connor
Tracy
T
Tiberi
Cinzia
C
Rehrauer
Hubert
H
Weis
Joachim
J
Aguzzi
Adriano
A
D000818:Animals; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics*; D004722:Endoribonucleases / Q000172:deficiency* / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology*; D043244:Ribonuclease III; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
Cell. 2009 Feb 20;136(4):642-55
19239886
J Exp Med. 2007 Jul 9;204(7):1553-8
17606634
Nucleic Acids Res. 2003 Sep 15;31(18):5405-12
12954777
J Neurosci. 2008 Nov 5;28(45):11720-30
18987208
Glia. 2009 Sep;57(12):1265-79
19170179
Brain. 2007 Oct;130(Pt 10):2703-14
17898011
EMBO J. 1988 Jun;7(6):1635-45
3049071
Nat Rev Neurosci. 2003 Sep;4(9):714-26
12951564
Cell. 1993 Dec 3;75(5):843-54
8252621
J Neurosci. 2010 May 12;30(19):6763-75
20463238
EMBO J. 2004 Aug 4;23(15):3061-71
15241478
Nat Neurosci. 2009 Jul;12(7):839-47
19525946
Nat Genet. 2003 Nov;35(3):215-7
14528307
J Pathol. 2010 Jan;220(1):58-70
19890883
PLoS One. 2010 May 05;5(5):e10480
20463920
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12135-40
16099834
J Neurosci. 2004 Jul 28;24(30):6724-32
15282275
Neuron. 2010 Mar 11;65(5):612-26
20223198
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9188-93
15967991
Nature. 2001 Jan 18;409(6818):363-6
11201747
J Neurosci. 2008 Apr 23;28(17):4322-30
18434510
Cancer Res. 2009 Oct 1;69(19):7569-76
19773441
Semin Cell Dev Biol. 2010 Sep;21(7):774-80
20152923
Nat Rev Neurosci. 2005 Sep;6(9):671-82
16136171
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903
16040801
Genes Chromosomes Cancer. 2009 Jul;48(7):569-82
19396866
Oncogene. 1995 Jul 20;11(2):325-35
7624147
Carcinogenesis. 2010 Jun;31(6):1037-44
20351093
Cell Cycle. 2010 Mar 15;9(6):1031-6
20190569
Nucleic Acids Res. 2005 Mar 01;33(4):1290-7
15741182
Genesis. 2007 Dec;45(12):768-75
18064676
Neuron. 2010 Mar 11;65(5):597-611
20223197