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

Kepa A, Medina LM, Erk S, Srivastava DP, Fernandes A, Toro R, Levi S, Ruggeri B, Fernandes C, Degenhardt F, Witt SH, Meyer-Lindenberg A, Poncer JC, Martinot JL, Martinot MLP, Müller CP, Heinz A, Walter H, Schumann G, Desrivieres S (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Neuropsychopharmacology Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 42

Pages Range: 2516-2526

Journal Issue: 13

DOI: 10.1038/npp.2017.91

Abstract

The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the etiology of neurodevelopmental disorders is increasingly recognized. 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 (1) MYT1L is required for neuronal differentiation and identified ID1, a HLH inhibitor of premature neurogenesis, as a target. (2) Although 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.

Authors with CRIS profile

Peter Christian Müller Professur für Suchtmedizin

Involved external institutions

King’s College London GB United Kingdom (GB) Charité - Universitätsmedizin Berlin DE Germany (DE) Institut Pasteur FR France (FR) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Zentralinstitut für Seelische Gesundheit DE Germany (DE)

How to cite

APA:

Kepa, A., Medina, L.M., Erk, S., Srivastava, D.P., Fernandes, A., Toro, R.,... Desrivieres, S. (2017). Associations of the Intellectual Disability Gene MYT1L with Helix-Loop-Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval. Neuropsychopharmacology, 42(13), 2516-2526. https://doi.org/10.1038/npp.2017.91

MLA:

Kepa, Agnieszka, et al. "Associations of the Intellectual Disability Gene MYT1L with Helix-Loop-Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval." Neuropsychopharmacology 42.13 (2017): 2516-2526.

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