Dataset Information

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

ABSTRACT: MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiologic defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Dimitris Papageorgiou

LAB HEAD: Jeroen Krijgsveld

PROVIDER: PXD037867 | Pride | 2023-02-20

REPOSITORIES: pride

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			Action	DRS
	20200626_FS1_DP_PM_IgG_604.raw	Raw
	20200626_FS1_DP_PM_IgG_605.raw	Raw
	20200626_FS1_DP_PM_IgG_606.raw	Raw
	20200627_FS1_DP_PM_IP_604.raw	Raw
	20200627_FS1_DP_PM_IP_605.raw	Raw

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MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention.

Weigel Bettina B Tegethoff Jana F JF Grieder Sarah D SD Lim Bryce B Nagarajan Bhuvaneswari B Liu Yu-Chao YC Truberg Jule J Papageorgiou Dimitris D Adrian-Segarra Juan M JM Schmidt Laura K LK Kaspar Janina J Poisel Eric E Heinzelmann Elisa E Saraswat Manu M Christ Marleen M Arnold Christian C Ibarra Ignacio L IL Campos Joaquin J Krijgsveld Jeroen J Monyer Hannah H Zaugg Judith B JB Acuna Claudio C Mall Moritz M

Molecular psychiatry 20230214 5

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including ...[more]

PMID: 36782060

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