A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Chen, Jiayang; Lambo, Mary E.; Ge, Xia; Dearborn, Joshua T.; Liu, Yating; McCullough, Katherine; Swift, Raylynn G; Tabachnick, Dora R.; Tian, Lucy; Noguchi, Kevin K.; Garbow, Joel R.; Gabel, Harrison W.; Hengen, Keith B.; Maloney, Susan E.; Dougherty, Joseph D.

doi:10.1101/2020.12.17.423095

Cited by 4 publications

(5 citation statements)

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“…However, a MYT1 proteomics study with Neuro2A cell identified LSD1-CoREST-PHF21A complex (48), which is consistent with our results and suggests plausible roles of the complex in the MYT-mediated transcriptional regulation of neurodevelopmental gene expression program. Furthermore, MYT1L can also activate the transcription of neuronal maturation genes with unknown mechanisms (25,49). It is tempting to speculate that the neuronal splicing of LSD1 and PHF21A is responsible for the functional switch of MYT1L from repressor to activator, with the neuronal LSD1-PHF21A complex acting as a dominant negative machinery.…”

Section: Discussionmentioning

confidence: 99%

Asynchronous microexon splicing ofLSD1andPHF21Aduring neurodevelopment

Nagai,

Porter,

Hughes

et al. 2024

Preprint

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LSD1 histone H3K4 demethylase and its binding partner PHF21A, a reader protein for unmethylated H3K4, both undergo neuron-specific microexon splicing. The LSD1 neuronal microexon weakens H3K4 demethylation activity and can alter the substrate specificity to H3K9 or H4K20. Meanwhile, the PHF21A neuronal microexon interferes with nucleosome binding. However, the temporal expression patterns of LSD1 and PHF21A splicing isoforms during brain development remain unknown. In this work, we report that neuronal PHF21A isoform expression precedes neuronal LSD1 isoform expression during human neuron differentiation and mouse brain development. The asynchronous splicing events resulted in stepwise deactivation of the LSD1-PHF21A complex in reversing H3K4 methylation. We further show that the enzymatically inactive LSD1-PHF21A complex interacts with neuron-specific binding partners, including MYT1-family transcription factors and post-transcriptional mRNA processing proteins such as VIRMA. The interaction with the neuron-specific components, however, did not require the PHF21A microexon, indicating that the neuronal proteomic milieu, rather than the microexon-encoded PHF21A segment, is responsible for neuron-specific complex formation. These results indicate that the PHF21A microexon is dispensable for neuron-specific protein-protein interactions, yet the enzymatically inactive LSD1-PHF21A complex might have unique gene-regulatory roles in neurons.

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Section: Discussionmentioning

confidence: 99%

Asynchronous microexon splicing ofLSD1andPHF21Aduring neurodevelopment

Nagai,

Porter,

Hughes

et al. 2024

Preprint

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“…The open field test was used to assess the general activity and approach/avoidance (anxiety-like) behaviors of mice at P40 over a 1-hour period, based on previously published methods 12,13 . The test was performed using a transparent, acrylic testing apparatus (50×50×50 cm) enclosed within a white sound-attenuating box with dim red lighting at 10 lux.…”

Section: Open Field Testmentioning

confidence: 99%

“…Social motivation, including social reward seeking and social orienting was evaluated from P83-P98 using a social operant task. Procedures used here were as described previously 12 (Fig. S2C) with minor alterations.…”

Section: Social Operantmentioning

confidence: 99%

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Perinatal Oxycodone Exposure Causes Long Term Sex-Dependent Changes in Sensory and Reward Processing in Adult Mice

Minakova

Mikati

Madasu

et al. 2022

Preprint

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In utero opioid exposure is associated with lower weight and a Neonatal Opioid Withdrawal Syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Therefore, we implemented a rodent perinatal opioid exposure model of Oxycodone (Oxy) exposure for comparison of long-term consequences of Oxy exposure until birth (Short Oxy) to the impact of continued postnatal opioid exposure (Long Oxy) spanning gestation through birth and lactation. Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males, sex-dependent changes in morphine conditioned place preference, and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following Short or Long Oxy exposure. Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

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“…The loss of FTSJ1 in humans gives rise to ID, yet the underlying mechanism is still unclear. Both neuronal morphology 76 and behaviour 27 have been reported in patients affected by a wide range of ID disorders, with a variety of genetic etiologies and their corresponding mouse models. To address whether loss of human FTSJ1 also affects neuronal morphology, we altered FTSJ1 activity using 2,6-Diaminopurine (DAP) 77,78 in human Neural Progenitor Cells (NPC).…”

Section: Ftsj1 Is Involved In Human Neuronal Morphology During Developmentmentioning

confidence: 99%

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

Dimitrova

Brazane

Pigeon

et al. 2021

Preprint

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FTSJ1 is a phyllogenetically conserved human 2-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the AntiCodon Loop (ACL) of specific tRNAs: tRNAPhe(GAA), tRNATrp(CCA) and tRNALeu(UAA). FTSJ1 loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently in cancers. However, the exact molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1 tRNA targets has not been fully addressed yet. We performed unbiased and comprehensive RiboMethSeq analysis of the Nm profiles for human tRNA population extracted from cells derived from NSXLID patients blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a de novo mutation in the FTSJ1 gene. Some of the newly identified FTSJ1 tRNA targets are also conserved in Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between deregulated miRNA and mRNA obtained in FTSJ1 mutants highlighted upregulation of miR10a-5p which has the capacity to silence the SPARC gene mRNA, downregulated in FTSJ1 mutant cells. This suggests that FTSJ1 loss may influence gene expression deregulation by modulation of miRNA silencing. A gene-ontology (GO) enrichment analysis of the deregulated mRNAs primarily matched to brain morphogenesis terms, followed by metabolism and translation related genes. In parallel, the deregulated miRNAs are mostly known for their implication in brain functions and cancers. Based on these results, we suggest that miRNA silencing variations may play a role in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight miR-181a-5p as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability.

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A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Cited by 4 publications

References 80 publications

Asynchronous microexon splicing ofLSD1andPHF21Aduring neurodevelopment

Asynchronous microexon splicing ofLSD1andPHF21Aduring neurodevelopment

Perinatal Oxycodone Exposure Causes Long Term Sex-Dependent Changes in Sensory and Reward Processing in Adult Mice

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

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