α1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window.
Animals
Calcium Channels
/ genetics
Calcium Channels, N-Type
/ genetics
Cerebellum
/ growth & development
Gene Expression Regulation, Developmental
/ genetics
Genetic Therapy
HEK293 Cells
HeLa Cells
Humans
Internal Ribosome Entry Sites
Mice
Mice, Transgenic
PC12 Cells
Rats
Spinocerebellar Ataxias
/ genetics
Transcription Factors
/ genetics
Transcription Initiation Site
CACNA1A
IRES
Purkinje cell
VGCC
bicistronic
cerebellum
development
gene-silencing
spinocerebellar ataxia type 6
transcription factor
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
22 05 2019
22 05 2019
Historique:
received:
29
05
2018
revised:
17
12
2018
accepted:
20
02
2019
pubmed:
30
3
2019
medline:
26
3
2020
entrez:
30
3
2019
Statut:
ppublish
Résumé
Postnatal cerebellar development is a precisely regulated process involving well-orchestrated expression of neural genes. Neurological phenotypes associated with CACNA1A gene defects have been increasingly recognized, yet the molecular principles underlying this association remain elusive. By characterizing a dose-dependent CACNA1A gene deficiency mouse model, we discovered that α1ACT, as a transcription factor and secondary protein of CACNA1A mRNA, drives dynamic gene expression networks within cerebellar Purkinje cells and is indispensable for neonatal survival. Perinatal loss of α1ACT leads to motor dysfunction through disruption of neurogenesis and synaptic regulatory networks. However, its elimination in adulthood has minimal effect on the cerebellum. These findings shed light on the critical role of α1ACT in facilitating neuronal development in both mice and humans and support a rationale for gene therapies for calcium-channel-associated cerebellar disorders. Finally, we show that bicistronic expression may be common to the voltage-gated calcium channel (VGCC) gene family and may help explain complex genetic syndromes.
Identifiants
pubmed: 30922876
pii: S0896-6273(19)30171-0
doi: 10.1016/j.neuron.2019.02.036
pmc: PMC6533132
mid: NIHMS1524031
pii:
doi:
Substances chimiques
CACNA1A protein, human
0
Cacna1a protein, rat
0
Calcium Channels
0
Calcium Channels, N-Type
0
Internal Ribosome Entry Sites
0
Transcription Factors
0
voltage-dependent calcium channel (P-Q type)
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
770-785.e7Subventions
Organisme : NINDS NIH HHS
ID : R01 NS082788
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS094665
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS094872
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Références
Brain Res Mol Brain Res. 1999 Nov 10;73(1-2):151-71
pubmed: 10581409
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15245-50
pubmed: 10611370
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
Genomics. 2001 Jun 15;74(3):287-98
pubmed: 11414756
J Cell Biol. 2001 Sep 17;154(6):1259-73
pubmed: 11564762
J Neurosci. 2003 Feb 1;23(3):883-94
pubmed: 12574417
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51
pubmed: 1319065
Cell. 2004 Oct 1;119(1):19-31
pubmed: 15454078
Nat Neurosci. 2004 Nov;7(11):1222-32
pubmed: 15494732
Nat Neurosci. 2004 Nov;7(11):1213-21
pubmed: 15494734
J Physiol. 2005 Sep 15;567(Pt 3):829-50
pubmed: 16002452
Hum Mol Genet. 2006 May 15;15(10):1587-99
pubmed: 16595610
Cell. 2006 Nov 3;127(3):591-606
pubmed: 17081980
Cell. 2006 Nov 17;127(4):697-708
pubmed: 17110330
Dev Biol. 2007 Mar 1;303(1):231-43
pubmed: 17150206
J Neurochem. 2007 Mar;100(6):1599-612
pubmed: 17212696
Arch Neurol. 2008 Jun;65(6):817-20
pubmed: 18541804
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11987-92
pubmed: 18687887
BMC Bioinformatics. 2008 Dec 29;9:559
pubmed: 19114008
Curr Opin Neurobiol. 2009 Apr;19(2):154-61
pubmed: 19481442
J Med Genet. 2009 Nov;46(11):786-91
pubmed: 19586927
Neurogenetics. 2010 Feb;11(1):101-6
pubmed: 19633872
Pflugers Arch. 2010 Jul;460(2):353-9
pubmed: 19916019
J Comp Neurol. 2010 Apr 1;518(7):1113-32
pubmed: 20127821
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
J Neurosci. 2010 Jun 23;30(25):8529-40
pubmed: 20573900
Nature. 2011 Apr 21;472(7343):356-60
pubmed: 21460838
PLoS One. 2011;6(6):e20791
pubmed: 21695168
Nat Genet. 2011 Aug 14;43(9):838-46
pubmed: 21841781
Seizure. 2012 Mar;21(2):79-86
pubmed: 22206818
Nat Rev Genet. 2012 Jul 18;13(8):552-64
pubmed: 22805708
BMC Genomics. 2012 Nov 12;13:610
pubmed: 23145530
Cell. 2013 Mar 14;152(6):1237-51
pubmed: 23498934
J Physiol. 2013 Jun 15;591(12):2987-98
pubmed: 23568894
Lancet. 2013 May 11;381(9878):1654-62
pubmed: 23663951
Cell. 2013 Jul 3;154(1):118-33
pubmed: 23827678
Front Genet. 2013 Nov 05;4:222
pubmed: 24204377
Cell Cycle. 2014;13(6):875-6
pubmed: 24552819
Neurobiol Dis. 2014 Aug;68:47-56
pubmed: 24768804
Cell Tissue Res. 2014 Aug;357(2):463-76
pubmed: 24996399
Nat Genet. 2014 Oct;46(10):1063-71
pubmed: 25217958
Development. 2014 Nov;141(21):4031-41
pubmed: 25336734
J Biol Chem. 2015 Feb 20;290(8):4663-76
pubmed: 25538241
ACS Chem Neurosci. 2015 Jul 15;6(7):1198-205
pubmed: 25642596
Eur J Hum Genet. 2015 Nov;23(11):1505-12
pubmed: 25735478
Eur J Neurosci. 2015 Oct;42(8):2499-507
pubmed: 25989111
Cell. 2015 Jul 16;162(2):412-424
pubmed: 26186193
Am J Med Genet A. 2015 Oct;167A(10):2334-43
pubmed: 26189583
PLoS One. 2015 Jul 23;10(7):e0133247
pubmed: 26204268
Cerebellum. 2016 Dec;15(6):789-828
pubmed: 26439486
Neuron. 2016 Mar 16;89(6):1194-1207
pubmed: 26948890
Sci Transl Med. 2016 Jul 13;8(347):347ra94
pubmed: 27412786
Biochem Biophys Res Commun. 2016 Sep 23;478(3):1429-35
pubmed: 27569278
Cell Rep. 2016 Nov 1;17(6):1482-1490
pubmed: 27806289
Trends Genet. 2017 Feb;33(2):129-142
pubmed: 28012572
Cell Rep. 2017 Jan 10;18(2):367-379
pubmed: 28076782
J Mol Endocrinol. 2017 Jul;59(1):R47-R63
pubmed: 28400483
Nature. 2017 May 18;545(7654):350-354
pubmed: 28445456
Nat Rev Neurosci. 2017 Oct;18(10):613-626
pubmed: 28855740
Stem Cells Dev. 2017 Nov 15;26(22):1612-1625
pubmed: 28946818
Cell. 2017 Oct 19;171(3):557-572.e24
pubmed: 29053968
Cerebellum. 2018 Feb;17(1):72-77
pubmed: 29374372
Adv Exp Med Biol. 2018;1049:147-173
pubmed: 29427102
Neuron. 2018 Nov 21;100(4):846-859.e7
pubmed: 30318414
Neuroscience. 1982;7(9):2185-96
pubmed: 7145091
Cell. 1996 Nov 15;87(4):607-17
pubmed: 8929530
J Neurosci. 1997 Nov 1;17(21):8506-19
pubmed: 9334423
Trends Neurosci. 1998 Sep;21(9):375-82
pubmed: 9735945