The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation.
Oligodendrocyte development is tightly controlled by a variety of extracellular growth and differentiation factors. The mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, are critical intracellular signaling molecules important for transducing these extracellular signals. The extracellular signal-regulated kinases (ERKs) are ubiquitously expressed, coordinately regulated, and highly similar, but Erk2 deletion in mice is embryonic lethal whereas Erk1 deletion is not. Several studies have suggested that MAPK signaling is important for oligodendrocyte differentiation, although specific roles for the two ERK isoforms have not been investigated. In this study, we deleted Erk2 in the developing mouse cortex from GFAP-expressing radial glia that generate neurons and oligodendrocytes. In vitro analysis revealed that loss of ERK2 resulted in fewer galactocerebroside-expressing mature oligodendrocytes in cortical cultures. In vivo, a delay in the expression of the myelin protein MBP was observed in the corpus callosum at postnatal day 10 (P10). In contrast, Erk1 deletion did not affect oligodendrocyte differentiation. By P21, MBP expression was restored to wild-type levels, demonstrating that the loss of ERK2 results in a delay but not a complete arrest in the appearance of differentiated oligodendrocytes in vivo. Importantly, both the proliferation and total number of oligodendrocyte progenitor cells (OPCs) appeared normal in the Erk2 conditional knock-out cortex, demonstrating that ERK2 plays a specific role in the timing of forebrain myelination but is not critical for the proliferation or survival of OPCs. Oligodendrocyte-specific deletion of Erk2 also resulted in decreased levels of MBP, indicating a cell-autonomous effect of ERK2 in the oligodendrocyte lineage.
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Sharyl L
SL
Fyffe-Maricich
J Colleen
JC
Karlo
Gary E
GE
Landreth
Robert H
RH
Miller
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
D019950:Mitogen-Activated Protein Kinase 1
Genesis. 2001 Oct;31(2):85-94
11668683
J Cell Biol. 2008 Mar 10;180(5):947-55
18332218
Brain. 2008 Jul;131(Pt 7):1749-58
18515322
J Neurosci Res. 2010 Mar;88(4):758-63
19830833
Nature. 1988 Jun 9;333(6173):560-2
3287176
Cell Regul. 1991 May;2(5):357-71
1654126
N Engl J Med. 2002 Jan 17;346(3):165-73
11796850
J Cell Biol. 1999 Dec 13;147(6):1123-8
10601327
J Neurosci Res. 1998 Dec 15;54(6):754-65
9856859
Trends Cell Biol. 1993 Jun;3(6):191-7
14731493
Biochimie. 2006 Sep;88(9):1091-8
16854512
J Neurosci. 2009 May 13;29(19):6367-78
19439614
J Neurosci Res. 2003 Nov 15;74(4):486-93
14598292
J Neurosci Res. 2006 Dec;84(8):1692-702
17044032
Neuron. 2002 May 30;34(5):807-20
12062026
J Neurosci. 2009 May 27;29(21):6860-70
19474313
J Neurochem. 2001 Mar;76(6):1925-34
11259511
Nat Neurosci. 2006 Feb;9(2):173-9
16388308
Brain. 1998 Dec;121 ( Pt 12):2221-8
9874475
J Neurochem. 1996 May;66(5):1986-94
8780027
J Neurosci. 1998 Jan 15;18(2):601-9
9425002
Trends Neurosci. 1996 Mar;19(3):92-6
9054062
Mol Cell Neurosci. 1996;8(1):38-52
8923454
J Cell Biol. 2010 Feb 8;188(3):305-12
20142420
Mol Cell Neurosci. 2003 Oct;24(2):476-88
14572468
EMBO Rep. 2003 Oct;4(10):964-8
14502223
Mol Cell Neurosci. 2006 Apr;31(4):676-84
16458536
Mol Cell Neurosci. 2000 Mar;15(3):314-29
10736207
Dev Biol. 1994 Apr;162(2):511-24
8150210
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12759-64
14566055
J Neurosci. 2008 Jul 2;28(27):6983-95
18596172
Cell. 1992 Jul 10;70(1):31-46
1623522
Mol Biotechnol. 2005 Oct;31(2):151-74
16170216
J Neurosci Res. 1991 Oct;30(2):382-90
1665869
Int J Dev Neurosci. 2009 Dec;27(8):757-68
19729058
Cell. 1991 May 17;65(4):663-75
2032290
Genes Cells. 2003 Nov;8(11):847-56
14622137
Neuron. 1990 Nov;5(5):603-14
2171589
J Immunol. 2005 Aug 15;175(4):2374-80
16081808
Nature. 1988 Jun 9;333(6173):562-5
3287177
J Neurosci Res. 1997 Dec 1;50(5):729-42
9418961