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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1l haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

Original languageEnglish
Pages (from-to)3775-3792.e14
JournalNeuron
Volume109
Issue number23
DOIs
StatePublished - Dec 1 2021

Keywords

  • ADHD
  • ASD
  • Autism
  • Chromatin Accessibility
  • Hyperactivity
  • ID
  • Neuronal Differentiation
  • Social Motivation
  • Transcription

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