The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons.
15q duplication autism
Angelman syndrome
Axonal guidance
Contact guidance
Cytoskeleton
Microgratings
Nocodazole
Ubiquitin ligase E3a (UBE3A)
Journal
Molecular autism
ISSN: 2040-2392
Titre abrégé: Mol Autism
Pays: England
ID NLM: 101534222
Informations de publication
Date de publication:
2019
2019
Historique:
received:
03
05
2019
accepted:
17
10
2019
entrez:
5
12
2019
pubmed:
5
12
2019
medline:
18
6
2020
Statut:
epublish
Résumé
Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity.
Sections du résumé
Background
Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway.
Methods
Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance.
Results
We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype.
Conclusions
We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity.
Identifiants
pubmed: 31798818
doi: 10.1186/s13229-019-0293-1
pii: 293
pmc: PMC6884852
doi:
Substances chimiques
Ube3a protein, mouse
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
41Informations de copyright
© The Author(s). 2019.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare that they have no competing interests.
Références
Neurobiol Dis. 2012 Aug;47(2):210-5
pubmed: 22525571
J R Soc Interface. 2012 Sep 7;9(74):2017-32
pubmed: 22753785
Paediatr Drugs. 2003;5(10):647-61
pubmed: 14510623
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):E1361-70
pubmed: 23515331
Nat Neurosci. 2019 Aug;22(8):1235-1247
pubmed: 31235931
Cell. 2015 Aug 13;162(4):795-807
pubmed: 26255772
Hum Mutat. 2015 Jul;36(7):689-93
pubmed: 25884337
J Neurosci. 2018 Sep 12;38(37):8011-8030
pubmed: 30082419
Biomaterials. 2013 Aug;34(25):6027-36
pubmed: 23694901
Mol Autism. 2019 May 22;10:23
pubmed: 31143434
J Clin Invest. 2015 May;125(5):2069-76
pubmed: 25866966
Curr Opin Neurobiol. 2014 Aug;27:89-95
pubmed: 24705242
PLoS One. 2016 Sep 14;11(9):e0162817
pubmed: 27626634
Nature. 2015 Oct 1;526(7571):50-1
pubmed: 26432241
Adv Healthc Mater. 2016 Apr 6;5(7):850-62
pubmed: 26845073
Dev Cell. 2012 Oct 16;23(4):729-44
pubmed: 23022035
Nat Rev Neurosci. 2014 Jan;15(1):7-18
pubmed: 24356070
Neurobiol Learn Mem. 2013 Sep;104:64-72
pubmed: 23707799
Nature. 2009 May 28;459(7246):569-73
pubmed: 19404257
J Neurosci. 2009 Apr 22;29(16):5183-92
pubmed: 19386914
J Cell Sci. 2011 Dec 15;124(Pt 24):4233-40
pubmed: 22193960
Mol Biol Cell. 2008 May;19(5):2147-53
pubmed: 18287519
Cell Motil Cytoskeleton. 2004 Jun;58(2):104-11
pubmed: 15083532
Adv Healthc Mater. 2013 Sep;2(9):1188-97
pubmed: 23713066
Front Hum Neurosci. 2013 Oct 22;7:671
pubmed: 24155705
Neuron. 1998 Oct;21(4):799-811
pubmed: 9808466
Dev Neurobiol. 2011 Nov;71(11):901-23
pubmed: 21714101
Front Neurosci. 2015 Sep 15;9:322
pubmed: 26441497
Interface Focus. 2014 Feb 6;4(1):20130047
pubmed: 24501675
Nat Rev Neurosci. 2011 May;12(5):251-68
pubmed: 21505515
Nat Rev Neurosci. 2007 Mar;8(3):194-205
pubmed: 17311006
Biomaterials. 2010 Jun;31(17):4682-94
pubmed: 20304485
PLoS One. 2010 Dec 30;5(12):e15966
pubmed: 21209862
Nanomaterials (Basel). 2018 Aug 10;8(8):
pubmed: 30103377
Am J Med Genet. 2001 Dec 8;105(8):675-85
pubmed: 11803514
Mol Cell Neurosci. 2017 Oct;84:4-10
pubmed: 28268126
Sci Rep. 2013;3:1141
pubmed: 23355954
Biomaterials. 2010 Mar;31(9):2565-73
pubmed: 20035995
Neuroimage. 2012 Jan 2;59(1):349-55
pubmed: 21827860
J Neurosci. 2018 Feb 21;38(8):1867-1873
pubmed: 29467146
PLoS One. 2013 Apr 23;8(4):e61952
pubmed: 23626758
Trends Neurosci. 2016 Jul;39(7):433-440
pubmed: 27233682
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5611-6
pubmed: 20212164
Nat Neurosci. 2009 Jun;12(6):777-83
pubmed: 19430469
Nat Neurosci. 2015 May;18(5):666-73
pubmed: 25867122
Nat Rev Mol Cell Biol. 2009 Jan;10(1):21-33
pubmed: 19197329
Nano Lett. 2011 Feb 9;11(2):505-11
pubmed: 21241061
J Neurosci. 2013 Jan 2;33(1):327-33
pubmed: 23283345
J Cell Biol. 2008 Feb 11;180(3):619-32
pubmed: 18268107
Trends Neurosci. 2013 Apr;36(4):218-26
pubmed: 23332798
Neuron. 2002 Aug 29;35(5):907-20
pubmed: 12372285
J Neurosci. 2018 Jan 10;38(2):363-378
pubmed: 29175955
J Biol Chem. 2004 Sep 24;279(39):41208-17
pubmed: 15263005
Neural Dev. 2009 Jul 14;4:26
pubmed: 19602271
Neurobiol Dis. 2009 Oct;36(1):26-34
pubmed: 19591933
Neuron. 2015 Dec 16;88(6):1208-1226
pubmed: 26671463
J Comp Neurol. 1982 Dec 1;212(2):208-13
pubmed: 7187917
J Neurosci. 2011 Aug 10;31(32):11678-91
pubmed: 21832197
Cell Struct Funct. 1996 Oct;21(5):317-26
pubmed: 9118237
Hum Mol Genet. 2008 Jan 1;17(1):111-8
pubmed: 17940072
Hum Mol Genet. 2009 Feb 1;18(3):454-62
pubmed: 18996915
Nanoscale. 2017 Oct 12;9(39):14861-14874
pubmed: 28948996
Nat Neurosci. 2007 Mar;10(3):280-2
pubmed: 17259980
J Neurosci. 2011 Sep 21;31(38):13585-95
pubmed: 21940449
Adv Healthc Mater. 2015 Aug 26;4(12):1849-60
pubmed: 26097140
J Neurosci. 1988 Apr;8(4):1454-68
pubmed: 3282038
Cell Rep. 2018 May 22;23(8):2429-2442
pubmed: 29791853
Adv Healthc Mater. 2014 Apr;3(4):581-7
pubmed: 24115396
Dev Neurosci. 2008;30(1-3):132-43
pubmed: 18075261