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Abstract

How neurons differentiate has been broadly studied during the past decades. However, comparably little is known about how postmitotic neurons maintain their cell fate throughout life, potentially preventing brain disorders. Unlike many other neurodevelopmental regulators, the neuron-specific transcription factor Myelin Transcription Factor 1-Like (MYT1L) is not only expressed during development but also in adulthood, suggesting a potential role in inducing and maintaining neuronal cell fate. Interestingly, MYT1L loss-of-function mutations are associated with neurodevelopmental disorders, referred to as MYT1L syndrome, and low levels of MYT1L have been linked to Alzheimer’s disease. Here, I investigate the role of MYT1L during development and in maintenance of neuronal cell fate and function later in life. Germline depletion of Myt1l caused neurodevelopmental defects, resulting in brain abnormalities, increased expression of non-neuronal genes, and electrophysiological hyperactivity. Interestingly, upregulation of the cardiac-specific sodium channel Scn5a was observed in Myt1l-mutant neurons, and knockdown of Scn5a normalised electrophysiological activity. Strikingly, acute treatment with the FDA-approved sodium channel blocker lamotrigine also rescued electric hyperactivity in vitro and even normalised behaviour hyperactivity in juvenile Myt1l-mutant mice. These results suggest lamotrigine treatment as a new therapeutic option for MYT1L syndrome. The finding that disease-associated phenotypes can be rescued later in life supports the hypothesis that MYT1L plays a dual role in inducing and maintaining neuronal fate and function. Therefore, I additionally investigated the role of Myt1l in postmitotic neurons. In mice, postnatal depletion of Myt1l phenocopied germline depletion causing behaviour hyperactivity and social impairment as well as upregulation of non-neuronal and early developmental genes, including early neurodevelopmental transcription factors. These changes were accompanied by epigenetic remodelling, resulting in open chromatin and reactivation of promoters and enhancers at early developmental genes. Together, my results show that continuous MYT1L-mediated repression of non-neuronal and early developmental genes is crucial to induce and maintain neuronal cell fate and function throughout life. Loss of this safeguarding mechanism in postmitotic neurons results in transcriptional and epigenetic reprogramming towards an immature, progenitor-like cell state, manifesting in disease-associated behaviour phenotypes in mice.