Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice

Kim, Seongbin; Oh, Hyoseon; Choi, Sang Tae; Yoo, Ye-Eun; Noh, Young Woo; Cho, Yisul; Im, Geun Ho; Lee, Chanhee; Oh, Yusang; Yang, Esther; Kim, Gyuri; Chung, Won‐Suk; Kim, Hyun; Kang, Hyojin; Bae, Yong-Chul; Kim, Seong‐Gi; Kim, Eunjoon

doi:10.1016/j.celrep.2022.111398

Cited by 15 publications

(18 citation statements)

References 97 publications

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“…Further, while Met expression is necessary for contextual fear memory in adults, embryonic deletion or reduction of Met had no impact on contextual fear memory expression through the late adolescent period. These findings were similar to behavioral deficits observed in adult, but not juvenile, mice that were haploinsufficient in Myt1l, a gene highly expressed early postnatally but not in adults [40]. In both instances, reduction in normal protein expression leads to the emergence of some behavioral deficits only after circuit maturation is complete, well beyond the period of normal peak protein expression.…”

Section: Discussionsupporting

confidence: 76%

Developmental and molecular contributions to contextual fear memory emergence in mice

Lanjewar

Levitt

Eagleson

2023

Preprint

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Cognitive impairment is a common phenotype of neurodevelopmental disorders, but how these deficits arise remains elusive. Determining the onset of discrete cognitive capabilities facilitates studies in probing mechanisms underlying their emergence. The present study analyzed the emergence of contextual fear memory persistence (7-day memory retention) and remote memory (30-day memory retention). There was a rapid transition from postnatal day (P) 20 to P21, in which memory persistence emerged in C57Bl/6J male and female mice. Remote memory was present at P23, but expression was not robust compared to pubertal and adult mice. To address a potential molecular mechanism, the present study examined the MET receptor tyrosine kinase (MET), which when deleted results in fear memory deficits in adult mice and regulates timing of critical period in the visual cortex, positioning it as a regulator for onset of contextual fear memory. Sustaining Met past the normal window of peak cortical expression or deleting Met did not alter the timing of emergence of persistence or remote memory capabilities. However, failure to exhibit fear memory occurred by P90 in mice with reduction or deletion of Met. Remarkably, the number of FOS-expressing infragranular neurons in medial prefrontal cortex (mPFC) did not increase with contextual conditioning at P35 but exhibited enhanced activation at P90. Additionally, MET-expressing neurons were preferentially recruited at P90 compared to P35 during fear memory expression. The studies demonstrate a developmental profile of contextual fear memory capabilities. Further, developmental disruption of Met leads to a delayed functional deficit that arises in adulthood.

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Section: Discussionsupporting

confidence: 76%

Developmental and molecular contributions to contextual fear memory emergence in mice

Lanjewar

Levitt

Eagleson

2023

Preprint

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“…This study showed that MYT1L heterozygous knockout (Het) mice recapitulate many phenotypes reminiscent of the human syndrome, including obesity, hyperactivity, and social deficits. Key phenotypes were replicated in two additional MYT1L haploinsufficiency mouse models (Wöhr et al 2022; Kim et al 2022). In the initial MYT1L germline knockout mouse line, it was also demonstrated that MYT1L loss results in insufficient cell proliferation in embryonic mouse cortex (Chen et al 2021).…”

Section: Introductionmentioning

confidence: 96%

MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain

Chen¹,

Fuhler

Noguchi

et al. 2022

Preprint

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In vitro studies indicate the neurodevelopmental disorder gene Myelin Transcription Factor 1 Like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L's molecular and cellular functions during differentiation in the mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) but down-regulated upper layer (UL) neuron gene expression, corresponding to an increased ratio of DL/UL neurons in mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets in mouse developing cortex and adult prefrontal cortex (PFC), and to map epigenetic changes due to MYT1L mutation. We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multi-omic dataset integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but does increase H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we show MYT1L interacts with SIN3B and HDAC2 in vivo, providing potential mechanisms underlying any repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights to how MYT1L facilitates neuronal maturation.

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“…Similarly, in vivo epigenetic studies of normal development show that MYT1L promotes neuronal differentiation by recruiting the SIN3B repressive complex to promoters and enhancers of postmitotic neurons to suppress early developmental programs 11 . Indeed, loss of MYT1L in multiple mouse models resulted in upregulation of a fetal gene expression signature [12][13][14] . To date, three pivotal studies have delved into the in vivo functions of MYT1L by creating transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

“…Each study uniquely disrupted a different exon of MYT1L (6 in Wohr et al 15 , 7 in Chen et al 12 , and 9 in Kim et al 13 ). The animal models are valuable tools to study the molecular and cellular consequences of MYT1L haploinsufficiency and the mice recapitulate many of the clinical presentations such as hyperactivity, structural malformations, obesity, and behavioral deficits [12][13][14] . However, it remains largely unknown how MYT1L haploinsufficiency influences the trajectory of neuronal differentiation in vivo, and whether the development of specific neuronal subtypes is particularly susceptible to the loss of MYT1L.…”

Section: Introductionmentioning

confidence: 99%

MYT1L deficiency impairs excitatory neuron trajectory during cortical development

Yen,

Chen,

Skinner

et al. 2024

Preprint

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Mutations that reduce the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. Furthermore, MYT1L is routinely used as a proneural factor in fibroblast-to-neuron transdifferentiation. MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss. In this study, we profiled 313,335 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete, to examine the role of MYT1L levels in the trajectory of neuronal development. We found that MYT1L deficiency significantly disrupted the relative proportion of cortical excitatory neurons at E14 and P21. Significant changes in gene expression were largely concentrated in excitatory neurons, suggesting that transcriptional effects of MYT1L deficiency are largely due to disruption of neuronal maturation programs. Most effects on gene expression were cell autonomous and persistent through development. In addition, while MYT1L can both activate and repress gene expression, the repressive effects were most sensitive to haploinsufficiency, and thus more likely mediate MYT1L syndrome. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

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Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice

Cited by 15 publications

References 97 publications

Developmental and molecular contributions to contextual fear memory emergence in mice

Developmental and molecular contributions to contextual fear memory emergence in mice

MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain

MYT1L deficiency impairs excitatory neuron trajectory during cortical development

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