MYT1L deficiency impairs excitatory neuron trajectory during cortical development

Allen Yen, Simona Sarafinovska, Xuhua Chen, Dominic D. Skinner, Fatjon Leti, MariaLynn Crosby, Jessica Hoisington-Lopez, Yizhe Wu, Jiayang Chen, Zipeng A. Li, Kevin K. Noguchi, Robi D. Mitra and Joseph D. Dougherty ()
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Allen Yen: Washington University School of Medicine
Simona Sarafinovska: Washington University School of Medicine
Xuhua Chen: Washington University School of Medicine
Dominic D. Skinner: Scale Biosciences
Fatjon Leti: Scale Biosciences
MariaLynn Crosby: Washington University School of Medicine
Jessica Hoisington-Lopez: Washington University School of Medicine
Yizhe Wu: Washington University School of Medicine
Jiayang Chen: Washington University School of Medicine
Zipeng A. Li: Washington University School of Medicine
Kevin K. Noguchi: Washington University School of Medicine
Robi D. Mitra: Washington University School of Medicine
Joseph D. Dougherty: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. MYT1L is used as a pro-neural factor in fibroblast-to-neuron transdifferentiation and is hypothesized to influence neuronal specification and maturation, but it is not clear which neuron types are most impacted by MYT1L loss. In this study, we profile 412,132 nuclei from the forebrains of wild-type and MYT1L-deficient mice at three developmental stages: E14 at the peak of neurogenesis, P1 when cortical neurons have been born, and P21 when neurons are maturing, to examine the role of MYT1L levels on neuronal development. MYT1L deficiency disrupts cortical neuron proportions and gene expression, primarily affecting neuronal maturation programs. Effects are mostly cell autonomous and persistent through development. While MYT1L can both activate and repress gene expression, the repressive effects are most sensitive to haploinsufficiency, likely mediating MYT1L syndrome. These findings illuminate MYT1L’s role in orchestrating gene expression during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

Date: 2024
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DOI: 10.1038/s41467-024-54371-2

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