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Associations of the Intellectual Disability Gene MYT1L with Helix-Loop-Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval

Research output: Contribution to journalArticle

Agnieszka Maria Kepa, Lourdes Martinez Medina, Susanne Erk, Deepak Prakash Srivastava, Alinda Fernandes, Roberto Toro, Sabine Lévi, Barbara Ruggeri, Catherine Fernandes, Franziska Degenhardt, Stephanie H. Witt, Andreas Meyer-Lindenberg, Jean-Christophe Poncer, Jean-Luc Martinot, Marie-Laure Paillere-Martinot, Christian P Müller, Andreas Heinz, Henrik Walter, Gunter Schumann, Sylvane Desrivieres

Original languageEnglish
Pages (from-to)2516–2526
JournalNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume42
Early online date7 Jun 2017
DOIs
Publication statusPublished - 2017

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Abstract

The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the aetiology of neurodevelopmental disorders is increasingly recognised. Yet, its function remains under-investigated. Here, we identify a network of helix-loop-helix (HLH) transcriptional regulators controlled by MYT1L, as indicated by our analyses in human neural stem cells and in the human brain. Using cell-based knockdown approaches and microarray analyses we found that (i) MYT1L is required for neuronal differentiation and identified ID1, a HLH inhibitor of premature neurogenesis, as a target. (2) While MYT1L prevented expression of ID1, it induced expression of a large number of terminal differentiation genes. (3) Consistently, expression of MYT1L in the human brain coincided with neuronal maturation and inversely correlated with that of ID1 and ID3 throughout the lifespan. (4) Genetic polymorphisms that reduced expression of MYT1L in the hippocampus resulted in increased expression of ID1 and ID3, decreased levels of the proneural basic HLH (bHLH) transcriptional regulators TCF4 and NEUROD6 and decreased expression of genes involved in long-term potentiation and synaptic transmission, cancer and neurodegeneration. Furthermore, our neuroimaging analyses indicated that MYT1L expression associated with hippocampal volume and activation during episodic memory recall, as measured by blood-oxygen-level dependent (BOLD) signals. Overall, our findings suggest that MYT1L influences memory-related processes by controlling a neuronal proliferation/differentiation switch of ID-bHLH factors.Neuropsychopharmacology accepted article preview online, 04 May 2017. doi:10.1038/npp.2017.91.

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