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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Publications

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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Project description:Inherited mutations of calcium ion channels exhibit neurological defects, such as epilepsy, ataxia, and migraine, and these phenotypes are shared among humans and mouse models. Absence epilepsy and ataxic phenotypes are present in the calcium channelopathy mutants stargazer (stg-gamma2 subunit), tottering (tg-alpha1 subunit), and lethargic (lh-beta4 subunit). These mutations of high-voltage-activated (HVA) calcium channel subunits initiate increases in membrane excitability of low-voltage-activated (LVA) calcium channels in thalamic neurons, thus enhancing LVA currents. Elevated LVA currents, produced from T-type calcium channels, induce rhythmic thalamocortical burst firing and spike-wave seizures. The changes in gene expression originating from the different mutations result in similar T-type channel function; however, the network of gene modifications causing altered molecular plasticity and the emergence of pathological phenotypes remain unknown. We would like to understand how loss of 3 different subunits of a calcium ion channel differentially alter gene expression in the brain. Characterizing the gene expression profiles of the mutant stg, tg, and lh mice will provide evidence of the epileptic and ataxic mechanisms, which may identify potential therapeutic targets. We will compare the gene expression profiles among adult mutant stg, tg, and lh mice, which display the ataxic and epileptic phenotypes, along with their wildtype, litter-mate controls, in the cerebellum and brain (without cerebellum). We propose that the neuronal dysfunction associated with the ataxic and epileptic phenotypes develops from a common network of interacting gene alterations within the mutant stg, tg, and lh brain. The changes dictated by the initial mutations leading to the ataxic and epileptic phenotypes are hypothesized to be localized to the cerebellum and the remaining areas of the brain, including the thalamus and cortex, respectively. Adult mutant stg, tg, and lh mice, between 2 and 5 months of age, along with wildtype, litter-mate controls, will be sacrificed. Two brain regions responsible for two phenotypes will be examined. The cerebellum (ataxia) will be dissected from remainder of the forebrain (generalized epilepsy). Each tissue set will be collected in triplicate (3 separate mice per set) to account for biological variance, and total RNA isolated via standard Trizol procedure (Invitrogen) and purified with the RNeasy cleanup kit (Qiagen). RNA samples will be stored at -80 C until sent for analysis using the Affymetrix GeneChip Mouse Genome 430 2.0 whole genome array.

Dataset Information

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

Publications

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

Similar Datasets

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