Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice.
Autism
Obesity
Social behavior
Transcription factor
Ultrasonic vocalization
Journal
Molecular autism
ISSN: 2040-2392
Titre abrégé: Mol Autism
Pays: England
ID NLM: 101534222
Informations de publication
Date de publication:
10 05 2022
10 05 2022
Historique:
received:
09
08
2021
accepted:
15
04
2022
entrez:
10
5
2022
pubmed:
11
5
2022
medline:
14
5
2022
Statut:
epublish
Résumé
The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.
Sections du résumé
BACKGROUND
The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity.
METHODS
Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied.
RESULTS
Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact.
LIMITATIONS
In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice.
CONCLUSIONS
Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.
Identifiants
pubmed: 35538503
doi: 10.1186/s13229-022-00497-3
pii: 10.1186/s13229-022-00497-3
pmc: PMC9087967
doi:
Substances chimiques
Myt1l protein, mouse
0
Nerve Tissue Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
19Subventions
Organisme : NIMH NIH HHS
ID : R01 MH115999
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Nat Protoc. 2018 Jun;13(6):1253-1274
pubmed: 29748649
Eur J Hum Genet. 2014 Apr;22(4):471-9
pubmed: 24129437
Mol Cytogenet. 2014 Aug 05;7:53
pubmed: 25126114
Clin Genet. 2013 Jul;84(1):31-6
pubmed: 23061379
Nature. 2016 Jun 08;534(7607):391-5
pubmed: 27281220
Cell. 2014 Jul 3;158(1):198-212
pubmed: 24995986
Cell. 1995 Mar 24;80(6):949-57
pubmed: 7697725
J Neurosci Res. 1997 Oct 15;50(2):272-90
pubmed: 9373037
J Dev Behav Pediatr. 2018 Jan;39(1):81-84
pubmed: 29293472
Am J Med Genet A. 2018 Sep;176(9):1972-1975
pubmed: 30055078
Nat Rev Neurosci. 2010 Jul;11(7):490-502
pubmed: 20559336
Am J Med Genet B Neuropsychiatr Genet. 2013 Apr;162B(3):273-82
pubmed: 23505263
Hippocampus. 2017 Aug;27(8):906-919
pubmed: 28500650
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17998-8003
pubmed: 19822762
Obes Res Clin Pract. 2021 Mar-Apr;15(2):124-132
pubmed: 33622623
Nat Neurosci. 2018 Nov;21(11):1515-1519
pubmed: 30349111
Transl Psychiatry. 2015 Mar 10;5:e525
pubmed: 25756808
Genes Brain Behav. 2012 Feb;11(1):87-93
pubmed: 21923761
PLoS Biol. 2005 Dec;3(12):e386
pubmed: 16248680
Nature. 2011 May 26;476(7359):220-3
pubmed: 21617644
J Cell Sci. 2016 Mar 15;129(6):1260-70
pubmed: 26818841
J Biol Chem. 1996 May 3;271(18):10723-30
pubmed: 8631881
Physiol Behav. 1981 Dec;27(6):1031-40
pubmed: 7335803
Neuron. 2019 Jun 5;102(5):993-1008.e5
pubmed: 31005376
Nat Rev Neurosci. 2016 Jan;17(1):45-59
pubmed: 26675822
Neurobiol Learn Mem. 2009 Sep;92(2):135-8
pubmed: 18854219
Am J Med Genet B Neuropsychiatr Genet. 2020 Jun;183(4):227-233
pubmed: 32267091
Nature. 2017 Apr 13;544(7649):245-249
pubmed: 28379941
Nature. 2017 Feb 23;542(7642):433-438
pubmed: 28135719
Genet Med. 2015 Aug;17(8):683-4
pubmed: 26240977
PLoS Genet. 2017 Aug 31;13(8):e1006957
pubmed: 28859103
Front Endocrinol (Lausanne). 2020 Feb 21;11:81
pubmed: 32153512
Genet Med. 2015 Jun;17(6):460-6
pubmed: 25232846
Behav Genet. 2008 Nov;38(6):579-95
pubmed: 18712592
Nat Commun. 2016 Nov 08;7:13316
pubmed: 27824329
Neuron. 2015 Sep 23;87(6):1215-1233
pubmed: 26402605
Mol Autism. 2015 Mar 08;6:13
pubmed: 25901271
Methods Mol Med. 2001;62:101-12
pubmed: 21318771
J Pediatr Endocrinol Metab. 2019 Apr 24;32(4):409-413
pubmed: 30796847
Am J Med Genet A. 2011 Nov;155A(11):2739-45
pubmed: 21990140
Neurosci Biobehav Rev. 2017 Sep;80:286-305
pubmed: 28579490
PLoS Biol. 2007 Jul;5(7):e173
pubmed: 17564499
Nature. 2014 Nov 13;515(7526):209-15
pubmed: 25363760
Cell Tissue Res. 2013 Oct;354(1):81-97
pubmed: 23576070
Behav Brain Res. 2013 Aug 15;251:5-17
pubmed: 23769995
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
Mol Cytogenet. 2018 Feb 05;11:14
pubmed: 29441128
Neurosci Biobehav Rev. 2020 Sep;116:31-43
pubmed: 32544538
Neuron. 2021 Dec 1;109(23):3775-3792.e14
pubmed: 34614421
J Comp Neurol. 1997 May 5;381(2):130-42
pubmed: 9130664
Autism Res. 2016 Jun;9(6):696-709
pubmed: 26419918
Psychiatr Genet. 2012 Jun;22(3):137-40
pubmed: 22157634
Dev Dyn. 2014 Apr;243(4):588-600
pubmed: 24214099
Am J Hum Genet. 2008 Oct;83(4):504-10
pubmed: 18940311
Psychiatr Genet. 2012 Aug;22(4):206-9
pubmed: 22547139
Genes Brain Behav. 2022 Jun;21(5):e12803
pubmed: 35285132
Am J Med Genet A. 2020 May;182(5):1021-1031
pubmed: 32065501
PLoS One. 2008 Aug 27;3(8):e3067
pubmed: 18728777
Stem Cell Reports. 2014 Aug 12;3(2):282-96
pubmed: 25254342
Behav Genet. 2005 Jan;35(1):19-29
pubmed: 15674530
Nature. 2010 Feb 25;463(7284):1035-41
pubmed: 20107439
Autism Res. 2021 Sep;14(9):1854-1872
pubmed: 34173729
Cell. 2020 Feb 6;180(3):568-584.e23
pubmed: 31981491