title: The role of MYT1L in the aetiology of neurodevelopmental disorders
creator: Weigel, Bettina
subject: ddc-500
subject: 500 Natural sciences and mathematics
description: Neurodevelopmental disorders (NDDs) represent a huge global health burden. However, the aetiology of most psychiatric disorders remains enigmatic, making it very difficult to  find adequate treatment options. While many transcription factors are associated with mental disorders, MYT1L stands out as one of very few life-long-expressed and neuronspecific transcriptional regulators. MYT1L mutations are closely linked to various neurodevelopmental disorders, like autism spectrum disorder and schizophrenia. In this work, I used embryonic stem cell-derived human neurons and mice to study how MYT1L regulates brain development, whether mutations are sufficient to cause mental disease and, if so, whether there is potential for therapeutic intervention.  I found that MYT1L deficiency caused upregulation of its target genes, including members of the WNT and NOTCH signalling pathways. This resulted in neurodevelopmental  delays that could be partially rescued by chemical pathway inhibition. MYT1L-deficient mice also presented with abnormal brain morphology and behavioural deficits. I found  that MYT1L loss caused upregulation of non-neuronal genes, including the main cardiac sodium channel SCN5A, which might explain the unexpected neuronal network hyperactivity observed in mouse and human neurons. Supporting this hypothesis, I was able to normalise electrophysiological hyperactivity by Myt1l overexpression and Scn5a knockdown.  Excitingly, the FDA-approved sodium channel blocker lamotrigine rescued electrophysiological abnormalities in vitro and behavioural deficits in vivo. The findings in this study show an important role of MYT1L as a transcriptional repressor not only during development but also after neurogenesis. Failure to silence non-neuronal gene expression in neurons might represent a novel mechanism that, at least in part, can contribute to NDD aetiology. The rescue of MYT1L deficiency-associated phenotypes in post-mitotic cells and adult mice opens up the possibility of therapeutic intervention for patients with MYT1L syndrome, including later in life.
date: 2023
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/33322/1/PhD_Thesis_Weigel.pdf
identifier: DOI:10.11588/heidok.00033322
identifier: urn:nbn:de:bsz:16-heidok-333224
identifier:   Weigel, Bettina  (2023) The role of MYT1L in the aetiology of neurodevelopmental disorders.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33322/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng