The autism-associated protein CHD8 is required for cerebellar development and motor function

Abstract

Highlights d CHD8 ablation in the brain of mice results in cerebellar hypoplasia d CHD8 regulates proliferation and differentiation of granule neuron progenitors (GNPs) d CHD8 loss in GNPs results in a motor function defect, but not in autism-like behavior d CHD8 is essential for the activation of neuronal gene expression in GNPs

Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

“…In both mouse and human, loss or mutations of CHD8 is known to lead to neurodevelopmental disorders ( Bernier et al, 2014 ; Durak et al, 2016 ; Kawamura et al, 2021 ; Kweon et al, 2021 ; Zhao et al, 2018 ). A recent paper found a significant association between anemia and neurodevelopmental disorders including autism spectrum disorder (ASD), attention-deficient/hyperactivity disorder (ADHD), and learning disability in a United States cohort ( Yang et al, 2021 ), but no information is available for the underlying mechanism of such anemia beyond diseaserelated behaviors affecting nutritional intake.…”

Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease

“…5 ; Egan et al 2013 ; Nitarska et al 2016 ). Likewise, both CHD7 ( Engelen et al 2011 ; Feng et al 2013 , 2017 ; Micucci et al 2014 ; Jones et al 2015 ; He et al 2016 ; Yao et al 2020 ) and CHD8 ( Sakamoto et al 2000 ; Nishiyama et al 2004 ; Ronan et al 2013 ; Sugathan et al 2014 ; Durak et al 2016 ; Katayama et al 2016 ; Kawamura et al 2021 ) are vital for brain development and regulate functions of stem cells in diverse brain regions. Thus, CHD enzymes play vital roles both in brain development (CHD2, CHD3/4/5, CHD7, and CHD8) and adult neurogenesis (CHD2, NuRD, and CHD7).…”

“…Beyond their role in regulating cell fate decisions during neurogenesis, CHD enzymes are also important for neuronal excitability (CHD2 [ Meganathan et al 2017 ] and CHD8 [ Platt et al 2017 ; Jung et al 2018 ; Ellingford et al 2021 ]), and for synaptic connectivity and strength (CHD4 [ Yamada et al 2014 ], CHD5 [ Egan et al 2013 ; Pisansky et al 2017 ], and CHD8 [ Platt et al 2017 ; Jung et al 2018 ; Ellingford et al 2021 ]). The CHD8 regulation of synaptic homeostasis and plasticity is vital for neocortical ( Kweon et al 2021 ) and cerebellar ( Kawamura et al 2021 ) development and is dysregulated in ASDs, as discussed below ( Fig. 5 ).…”

The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders

“…In a very recent study, Kawamura et al [67] performed specific knockout of CHD8 in cerebellar granule neuron precursors, using the Atoh-promoter-driven Cre line. These mice displayed decreases in the proliferation of precursor cells and decreases in neuronal differentiation.…”