Chd8 haploinsufficiency leads to molecular layer heterotopias and age-dependent cortical expansion
Year: 2026
Type: preprint
Abstract: Summary Mutations in the chromatin remodeler CHD8 are associated with autism and macrocephaly. While mouse models of Chd8 haploinsufficiency recapitulate brain overgrowth, the specific cellular mechanisms and developmental timing that lead to these anatomical abnormalities remain poorly understood. Here, we conducted 3D imaging of Chd8 V986*/+ mouse brains using magnetic resonance imaging followed by tissue clearing and cellular resolution light-sheet microscopy across embryonic and postnatal developmental stages. We found that brain overgrowth occurs postnatally, driven by an increase in non-neuronal cells prior to volumetric expansion. Unexpectedly, we identified prevalent molecular layer heterotopias (MLH) within the frontal cortex of Chd8 V986*/+ mice composed of neurons breaking through the pial surface during embryonic development and persisting throughout life. Increased incidence of MLH, previously identified in individuals with idiopathic autism, was replicated across three independent Chd8 +/- mouse models and present across multiple genomic backgrounds, establishing aberrant neuronal migration as a core feature of Chd8 haploinsufficiency.
Authors: Felix A Kyere, Ian Curtin, Ziquan Wei, Cesar P Canales, Nicolas Seban, Lei Xing, Preslava P Todorova, Leticia Pérez-Sisqués, Maya Yilan Yin, Tao Wen, Roza M Vlasova, Dirgha Sheth, Jeffrey Bennett, Kejia Li, Nana Matoba, Carolyn M McCormick, Tala Farah, Oleh Krupa, Madison R Glass, Bonnie Taylor-Blake, Eric S McCoy, Tzu-Wen Winnie Wang, Qiuhong He, Mustafa Dere, Brooke R. D’Arcy, Liam T Davis, Veda Dayananda, Carla Escobar-Tomlienovich, Karthik Eswar, Maryam Moghul, Meghana Yeturi, Karen Huang, Micah Baldonado, Mihir Kaikini, David G Amaral, Debra L. Silver, David Borland, Hong Yi, Pablo Ariel, Yen-Yu Ian Shih, M Albert Basson, Laura C Andreae, Alex S Nord, Mark J Zylka, Guorong Wu, Jason L Stein
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: The influence of common genetic variation on brain overgrowth pathways, Quantifying the developmental trajectory of autism-associated brain overgrowth using 3D cellular resolution imaging, AVANCE NEO upgrade for the BioSpec 9.4T/30cm MRI system at UNC, UNC Neuroscience Center Research Cores, 9.4T Small Animal MRI scanner at UNC, Clinical Translational Research Center for Neurodevelopmental Disorders, G9000121760, G9000199430, G9000210012, Molecular and Circuit Pathogenesis of Alcohol Use Disorders, Boss: A cloud-based data archive for electron microscopy and x-ray microtomography, Cancer Center Support Grant
OpenAlex ID: W7162764141