title: c-Jun N-terminal kinase regulates mGluR-dependent expression of post-synaptic FMRP target proteins.
abstract: Fragile X syndrome (FXS) is caused by the loss of functional fragile X mental retardation protein (FMRP). Loss of FMRP results in an elevated basal protein expression profile of FMRP targeted mRNAs, a loss of local metabotropic glutamate receptor (mGluR)-regulated protein synthesis, exaggerated long-term depression and corresponding learning and behavioral deficits. Evidence shows that blocking mGluR signaling in FXS models ameliorates these deficits. Therefore, understanding the signaling mechanisms downstream of mGluR stimulation may provide additional therapeutic targets for FXS. Kinase cascades are an integral mechanism regulating mGluR-dependent protein translation. The c-Jun N-terminal kinase (JNK) pathway has been shown to regulate mGluR-dependent nuclear transcription; however, the involvement of JNK in local, synaptic signaling has not been explored. Here, we show that JNK is both necessary and sufficient for mGluR-dependent expression of a subset of FMRP target proteins. In addition, JNK activity is basally elevated in fmr1 knockout mouse synapses, and blocking JNK activity reduces the over-expression of post-synaptic proteins in these mice. Together, these data suggest that JNK may be an important signaling mechanism downstream of mGluR stimulation, regulating FMRP-dependent protein synthesis. Furthermore, local, post-synaptic dysregulation of JNK activity may provide a viable target to ameliorate the deficits involved in FXS. Expression of many FMRP target proteins is enhanced in FXS. Here, we evaluated the role of JNKs in FXS. We found that JNK signaling is activated upon mGluR stimulation in wild-type neurons. Conversely, JNK activity is basally elevated in fmr1 knockout. Inhibiting JNK reduced the expression of FMRP target proteins and driving JNK activity increased the expression of these proteins.
authors.affiliation: Department of Pediatrics and the Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Travis L
authors.initials: TL
authors.lastname: Schmit
authors.forename: James A
authors.initials: JA
authors.lastname: Dowell
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Maes
authors.forename: Michael
authors.initials: M
authors.lastname: Wilhelm
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D004789:Enzyme Activation; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D048031:JNK Mitogen-Activated Protein Kinases; D018094:Receptors, Metabotropic Glutamate
keywords: FMRP; JNK; fragile X Syndrome; synapse
references.citation: Annu Rev Med. 2011;62:411-29
references.pmid: 21090964
references.citation: J Neurosci. 2010 Jan 13;30(2):694-702
references.pmid: 20071534
references.citation: Int J Oncol. 2012 Feb;40(2):577-82
references.pmid: 22076560
references.citation: PLoS Biol. 2007 Mar;5(3):e52
references.pmid: 17298186
references.citation: Acta Neuropathol. 1999 Mar;97(3):275-8
references.pmid: 10090675
references.citation: Science. 1991 Jun 21;252(5013):1711-4
references.pmid: 1675488
references.citation: Science. 2000 May 19;288(5469):1254-7
references.pmid: 10818003
references.citation: Neuron. 2008 Jul 10;59(1):70-83
references.pmid: 18614030
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Hum Mol Genet. 2000 Apr 12;9(6):901-8
references.pmid: 10767313
references.citation: J Neurosci. 2007 Oct 3;27(40):10685-94
references.pmid: 17913902
references.citation: Nat Neurosci. 2013 Nov;16(11):1530-6
references.pmid: 23584741
references.citation: Diabetes. 2001 Jan;50(1):77-82
references.pmid: 11147798
references.citation: Subcell Biochem. 2007;43:77-98
references.pmid: 17953392
references.citation: Nat Neurosci. 2012 Jan 22;15(3):431-40, S1
references.pmid: 22267161
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
references.pmid: 12032354
references.citation: Neuropsychopharmacology. 2012 Jan;37(1):178-95
references.pmid: 21796106
references.citation: J Neurosci. 2001 Oct 1;21(19):7551-60
references.pmid: 11567045
references.citation: J Neurosci. 2010 Nov 17;30(46):15616-27
references.pmid: 21084617
references.citation: J Alzheimers Dis. 2011;26(2):315-29
references.pmid: 21628793
references.citation: J Biol Chem. 2007 Jan 12;282(2):1288-95
references.pmid: 17095503
references.citation: J Biol Chem. 2012 Jan 13;287(3):2247-56
references.pmid: 22128169
references.citation: J Neurosci. 2007 May 16;27(20):5338-48
references.pmid: 17507556
references.citation: J Neurochem. 2009 Nov;111(3):635-46
references.pmid: 19659572
references.citation: Science. 1993 Oct 22;262(5133):563-6
references.pmid: 7692601
references.citation: J Med Genet. 2008 Aug;45(8):498-9
references.pmid: 18413371
references.citation: J Neurosci. 2008 Jan 9;28(2):543-7
references.pmid: 18184796
references.citation: Neurobiol Dis. 2005 Dec;20(3):685-93
references.pmid: 15949941
references.citation: Int J Clin Exp Pathol. 2009 Oct 10;3(1):56-68
references.pmid: 19918329
references.citation: Trends Mol Med. 2007 Oct;13(10):443-8
references.pmid: 17913584
references.citation: J Biol Chem. 1998 Jun 19;273(25):15521-7
references.pmid: 9624140
references.citation: Brain Res. 2011 Mar 22;1380:106-19
references.pmid: 21078304
references.citation: Psychopharmacology (Berl). 2011 May;215(2):291-300
references.pmid: 21181121
references.citation: J Biol Chem. 2011 Dec 23;286(51):43871-43880
references.pmid: 22033930
references.citation: Neuron. 2011 Jan 13;69(1):22-32
references.pmid: 21220096
references.citation: J Neurosci. 2007 Dec 26;27(52):14349-57
references.pmid: 18160642
references.citation: Curr Opin Neurobiol. 2009 Jun;19(3):319-26
references.pmid: 19411173
references.citation: Trends Neurosci. 2004 Jul;27(7):370-7
references.pmid: 15219735
references.citation: J Neurosci. 2004 May 19;24(20):4859-64
references.pmid: 15152046
references.citation: J Biol Chem. 2008 Jul 4;283(27):18478-82
references.pmid: 18474609
references.citation: Mol Cell. 2011 Jun 10;42(5):673-88
references.pmid: 21658607
references.citation: Science. 1991 May 24;252(5009):1179-81
references.pmid: 2031189
references.citation: Curr Alzheimer Res. 2010 May;7(3):200-6
references.pmid: 20088809
references.citation: Nat Med. 2003 Sep;9(9):1180-6
references.pmid: 12937412
references.citation: Sci Signal. 2008 Feb 05;1(5):pe6
references.pmid: 18272470
references.citation: Prog Mol Biol Transl Sci. 2012;106:145-69
references.pmid: 22340717
references.citation: Neuropharmacology. 2005 Dec;49(7):1053-66
references.pmid: 16054174
references.citation: J Neurosci Res. 2007 Jun;85(8):1668-73
references.pmid: 17455299
references.citation: Cell. 1991 Dec 20;67(6):1047-58
references.pmid: 1760838
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7337-42
references.pmid: 9207092
references.citation: J Neurosci. 2006 Jan 18;26(3):971-80
references.pmid: 16421317