The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective
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Cellular and Molecular Life Sciences
REVIEW
The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective Britt Mossink1,2 · Moritz Negwer1,2 · Dirk Schubert2 · Nael Nadif Kasri1,2 Received: 7 August 2020 / Revised: 4 November 2020 / Accepted: 16 November 2020 © The Author(s) 2020
Abstract Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDDassociated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies. Keywords Epigenetics · Transcriptional regulation · Neurodevelopment · Radial glia · Neural progenitor · Chromatin accessibility
Introduction A mature brain is the product of its development. Early developmental insults during the assembly of these neuronal circuits can severely impact how a person develops and behaves in their adult life. Across the ongoing developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation, early developmental insults will compound over time, leading to a circuit dysfunction.
Britt Mossink and Moritz Negwer have contributed equally to this work. * Nael Nadif Kasri [email protected] 1
Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands
2
Neurodevelopmental disorders (NDDs) pose such an example of disorders where early developmental insults from conception on result in a wide and heterogeneous spectrum of clinical diagnosis’s including intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ) and mood disorders (bipolar disorder (BD), major depressive disorder (MDD) [1]. These NDDs are often diagnosed during childhood, and overlap between diagnostic categories [2]. NDDs can be caused by both genetic and non-genetic sources. The most frequent non-genetic cause of NDDs is f
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