Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus.
Animals
Astrocytes
/ metabolism
Encephalitis
/ genetics
Female
GABAergic Neurons
/ metabolism
Gliosis
/ metabolism
Inflammation Mediators
/ metabolism
Interneurons
/ metabolism
Male
Mice, Knockout
Microglia
/ metabolism
Neural Stem Cells
/ metabolism
Transcriptome
WW Domain-Containing Oxidoreductase
/ genetics
Astrogliosis
Epilepsy
GABA-ergic interneurons
Hippocampus
Microgliosis
Wwox
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
09
05
2018
revised:
18
09
2018
accepted:
30
09
2018
pubmed:
6
10
2018
medline:
22
11
2019
entrez:
6
10
2018
Statut:
ppublish
Résumé
The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified 'neurological disease' and 'CNS development related functions' to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
Identifiants
pubmed: 30290271
pii: S0969-9961(18)30661-2
doi: 10.1016/j.nbd.2018.09.026
pmc: PMC7104842
mid: NIHMS1555635
pii:
doi:
Substances chimiques
Inflammation Mediators
0
WW Domain-Containing Oxidoreductase
EC 1.1.1.-
Wwox protein, mouse
EC 1.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
163-176Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Nat Rev Neurosci. 2006 Jul;7(7):548-62
pubmed: 16791144
PLoS One. 2009 Nov 10;4(11):e7775
pubmed: 19936220
Nat Genet. 2002 Apr;30(4):441-5
pubmed: 11889467
Am J Med Genet A. 2014 Nov;164A(11):2914-21
pubmed: 25124326
Orphanet J Rare Dis. 2014 Jan 23;9:12
pubmed: 24456803
Eur J Paediatr Neurol. 2018 May;22(3):516-524
pubmed: 29422393
Nat Genet. 2015 Apr;47(4):393-399
pubmed: 25751627
J Biol Chem. 2010 Oct 15;285(42):32160-73
pubmed: 20696761
Trends Neurosci. 2013 Mar;36(3):174-84
pubmed: 23298414
J Med Genet. 2017 Jul;54(7):460-470
pubmed: 28377535
Neurology. 2007 Feb 6;68(6):409-14
pubmed: 17283313
Pediatr Neurol. 2017 Oct;75:87-90
pubmed: 28811059
Brain. 2017 Sep 1;140(9):2337-2354
pubmed: 29050392
Pharmacogenomics. 2013 Nov;14(15):1849-56
pubmed: 24236484
Trends Neurosci. 1999 Jan;22(1):25-30
pubmed: 10088996
Nat Rev Neurosci. 2013 Jun;14(6):383-400
pubmed: 23686171
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14490-5
pubmed: 20651251
Mol Cell Neurosci. 2004 Apr;25(4):650-63
pubmed: 15080894
Am J Med Genet. 1999 Oct 29;86(5):482-5
pubmed: 10508992
Brain Res Mol Brain Res. 1995 Dec 28;34(2):190-6
pubmed: 8750822
Nat Rev Neurol. 2011 Jan;7(1):31-40
pubmed: 21135885
Neurology. 2016 Nov 8;87(19):1975-1984
pubmed: 27733563
Nat Genet. 2014 Dec;46(12):1327-32
pubmed: 25362483
Brain. 2014 Feb;137(Pt 2):411-9
pubmed: 24369382
Cell. 2010 Mar 19;140(6):918-34
pubmed: 20303880
Hippocampus. 1994 Jun;4(3):239-42
pubmed: 7842043
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):14060-5
pubmed: 9391152
Biochim Biophys Acta. 2014 Aug;1846(1):188-200
pubmed: 24932569
Am J Med Genet A. 2015 Dec;167A(12):3209-13
pubmed: 26345274
Ann Neurol. 2014 Jan;75(1):147-54
pubmed: 24272827
BMC Med Genomics. 2018 Feb 01;11(1):6
pubmed: 29390993
Nat Protoc. 2012 Nov;7(11):2005-12
pubmed: 23080272
Nature. 1996 May 30;381(6581):415-21
pubmed: 8632796
Annu Rev Pharmacol Toxicol. 2010;50:295-322
pubmed: 20055706
Metab Brain Dis. 2016 Aug;31(4):901-7
pubmed: 27121845
Cell Death Differ. 2012 Jun;19(6):1049-59
pubmed: 22193544
Exp Neurol. 2013 Jun;244:51-8
pubmed: 22178301
Oncogene. 2017 Apr 20;36(16):2215-2227
pubmed: 27869163
Neurosci Bull. 2014 Dec;30(6):985-998
pubmed: 25370443
Epilepsia. 2008;49 Suppl 2:33-41
pubmed: 18226170
Neurology. 2001 Oct 9;57(7):1191-8
pubmed: 11591834
Am J Med Genet B Neuropsychiatr Genet. 2012 Oct;159B(7):760-71
pubmed: 22825934
Seizure. 2017 Oct;51:74-76
pubmed: 28806589
Nat Genet. 1995 Sep;11(1):45-51
pubmed: 7550313
BMC Med Genet. 2016 Aug 05;17(1):53
pubmed: 27495153
Neuroscience. 2004;124(4):831-9
pubmed: 15026124
Trends Neurosci. 1994 Sep;17(9):373-9
pubmed: 7529442
Front Cell Neurosci. 2013 Sep 13;7:152
pubmed: 24062643
Eur J Paediatr Neurol. 2016 Jul;20(4):657-60
pubmed: 27117551
Am J Hum Genet. 2016 Sep 1;99(3):540-554
pubmed: 27569545
Nat Genet. 2010 Nov;42(11):1021-6
pubmed: 20890276
Brain. 2007 Jul;130(Pt 7):1921-8
pubmed: 17470496
Eur J Neurosci. 2000 Jul;12(7):2333-44
pubmed: 10947812
Eur J Hum Genet. 2004 Sep;12(9):701-5
pubmed: 15199382
Development. 2005 Jun;132(12):2917-27
pubmed: 15930120
Genesis. 2004 May;39(1):52-7
pubmed: 15124227
Clin Genet. 2015 Feb;87(2):e1-3
pubmed: 25477152
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
J Med Genet. 2015 Jan;52(1):61-70
pubmed: 25411445
Epilepsy Curr. 2013 Jul;13(4):172-6
pubmed: 24009481
J Neurol Sci. 2006 Aug 15;247(1):1-9
pubmed: 16697014
Sci Rep. 2015 Dec 07;5:17807
pubmed: 26639668
Sci Rep. 2015 Jan 28;5:8075
pubmed: 25627672
Neuron. 2014 Jan 22;81(2):229-48
pubmed: 24462092
J Hum Genet. 2015 May;60(5):267-71
pubmed: 25716914
Neurology. 2004 May 25;62(10):1857-61
pubmed: 15159495
Front Cell Neurosci. 2015 Jan 08;8:447
pubmed: 25620912
Neurology. 2002 Aug 13;59(3):348-56
pubmed: 12177367
Nephron Physiol. 2011;119(3):p40-8
pubmed: 21849804
J Biol Chem. 2004 Jul 16;279(29):30498-506
pubmed: 15126504
Neurology. 1994 Nov;44(11 Suppl 8):S14-23
pubmed: 7970002
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
J Neurosci. 2003 Mar 15;23(6):2440-52
pubmed: 12657704
Cell Mol Life Sci. 2009 Dec;66(23):3777-85
pubmed: 19707855
Hum Mol Genet. 2000 Jul 1;9(11):1651-63
pubmed: 10861292
Neuropeptides. 2013 Dec;47(6):431-8
pubmed: 24215800
J Mol Histol. 2006 May;37(3-4):115-25
pubmed: 16941225
Neuroscience. 1992;47(1):63-8
pubmed: 1315938
Hum Mol Genet. 2003 Jul 1;12(13):1463-74
pubmed: 12812975
Transl Psychiatry. 2017 Aug 1;7(8):e1188
pubmed: 28763065
Prog Neuropsychopharmacol Biol Psychiatry. 1993 Nov;17(6):887-903
pubmed: 8278600
J Biol Chem. 2010 Nov 12;285(46):36040-8
pubmed: 20807765
J Neurosci. 2005 Oct 19;25(42):9782-93
pubmed: 16237182
J Mol Neurosci. 2015 May;56(1):17-23
pubmed: 25403906
Cell. 2016 Feb 11;164(4):644-55
pubmed: 26871630
Genes Brain Behav. 2009 Oct;8(7):650-60
pubmed: 19500159
Oncotarget. 2014 Dec 15;5(23):11792-9
pubmed: 25537520
J Physiol. 2007 Mar 1;579(Pt 2):445-64
pubmed: 17204505
Cancer Res. 2000 Apr 15;60(8):2140-5
pubmed: 10786676