Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.
in utero electroporation
KIF2A
apoptosis
cortex
hippocampus
knock-in
malformations of cortical development
microtubule dynamics
mouse model
neuronal migration
videomicroscopy
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
27 03 2020
27 03 2020
Historique:
received:
12
08
2019
revised:
04
12
2019
accepted:
20
12
2019
pubmed:
11
1
2020
medline:
6
7
2021
entrez:
11
1
2020
Statut:
ppublish
Résumé
By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
Identifiants
pubmed: 31919497
pii: 5698694
doi: 10.1093/hmg/ddz316
pmc: PMC7104682
doi:
Substances chimiques
Repressor Proteins
0
KIF2A protein, mouse
EC 3.6.1.-
Kinesins
EC 3.6.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
766-784Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Cell. 1999 Jan 8;96(1):69-78
pubmed: 9989498
Annu Rev Cell Dev Biol. 2013;29:417-41
pubmed: 23875646
J Neurosci. 2014 Jan 22;34(4):1115-26
pubmed: 24453304
Mol Biol Cell. 2006 Feb;17(2):700-10
pubmed: 16291860
Bio Protoc. 2016 Jul 5;6(13):
pubmed: 28573158
Hum Mol Genet. 2018 Jan 15;27(2):224-238
pubmed: 29077851
Elife. 2018 Jan 09;7:
pubmed: 29313800
Genesis. 2006 Aug;44(8):355-60
pubmed: 16847871
Neurobiol Dis. 2016 Aug;92(Pt A):18-45
pubmed: 26299390
Genes Dev. 1991 Sep;5(9):1513-23
pubmed: 1653172
Cell Rep. 2017 Sep 12;20(11):2626-2638
pubmed: 28903043
Neuroscience. 2001;103(4):865-72
pubmed: 11301197
Nat Biotechnol. 2003 May;21(5):562-5
pubmed: 12665802
Development. 2007 Jun;134(12):2273-82
pubmed: 17507397
Ann Hematol. 2017 Sep;96(9):1485-1491
pubmed: 28616658
Seizure. 2011 Jun;20(5):359-68
pubmed: 21292505
Open Biol. 2019 Jun 28;9(6):180265
pubmed: 31185809
Curr Protoc Neurosci. 2016 Jan 04;74:3.29.1-3.29.23
pubmed: 26729032
Curr Biol. 2013 Jul 8;23(13):1215-20
pubmed: 23791725
Cell. 2003 Jul 25;114(2):229-39
pubmed: 12887924
Nat Genet. 2013 Jun;45(6):639-47
pubmed: 23603762
Cancer Cell. 2016 Sep 12;30(3):404-417
pubmed: 27622333
Front Cell Neurosci. 2014 Nov 14;8:386
pubmed: 25452716
Protein Expr Purif. 2003 Nov;32(1):83-8
pubmed: 14680943
Nat Commun. 2018 Jul 6;9(1):2628
pubmed: 29980677
Hum Mol Genet. 2001 Sep 15;10(19):2061-7
pubmed: 11590123
Biochimie. 2012 Nov;94(11):2193-201
pubmed: 22564826
J Biol Chem. 2001 Sep 14;276(37):34753-8
pubmed: 11466324
Genesis. 2006 Dec;44(12):611-21
pubmed: 17146780
Mol Med Rep. 2014 Jan;9(1):273-8
pubmed: 24248467
Neurogenetics. 2017 Apr;18(2):73-79
pubmed: 27747449
Front Cell Neurosci. 2014 Mar 04;8:63
pubmed: 24624057
Wiley Interdiscip Rev Dev Biol. 2014 Mar-Apr;3(2):165-77
pubmed: 24719288
Nat Cell Biol. 2013 Jul;15(7):731-40
pubmed: 23666084
Development. 2010 Jun;137(11):1907-17
pubmed: 20460369
Mol Genet Genomic Med. 2016 Sep 28;4(6):599-603
pubmed: 27896282
Cell Rep. 2013 Mar 28;3(3):759-68
pubmed: 23434508
Annu Rev Anim Biosci. 2017 Feb 8;5:371-389
pubmed: 28199172
Curr Protoc Mouse Biol. 2018 Sep;8(3):e48
pubmed: 29944194
Brain Struct Funct. 2019 Jan;224(1):33-56
pubmed: 30242506
Neurology. 2010 May 18;74(20):1575-82
pubmed: 20479356
PLoS One. 2019 Mar 13;14(3):e0213660
pubmed: 30865697