We didn't investigate behavioral phenotypes in our model. However our collaborator Rebecca Muhle is studying that question so keep an eye out for results from her group.

Thanks to the SFARI, @simonsfoundation.org, NOMIS Foundation, NICHD, NIGMS, NIMH, Charles H Hood Foundation, and NSF for supporting this work and making this paper possible!

This paper has been a massive undertaking, as can be appreciated by the changes between the published paper and our original preprint: doi.org/10.1101/2024...

Thanks to @krishnaswamylab.bsky.social and David van Dijk (@vandijklab.bsky.social), who developed a core method in the paper, PHATE, and helped with data analysis in the early phases of the project.

Congratulations to lead authors Kristi Yim, Marybeth Baumgartner (@baumoflife.bsky.social), and Martina Krenzer, in addition to co-authors María Rosales Larios, Mina Hill-Terán, Tim Nottoli, and @rebeccamuhle.bsky.social for their impressive work and perseverance on this project!

These findings suggest that CHD8 loss of function impacts gene regulatory networks and neurogenic potential of early radial glia, with distinct impacts on synaptic development and synaptic signaling of maturing excitatory neurons later in cortical development.

Across excitatory neuron subtypes of the maturing cortex, we detected dysregulation of synaptogenesis, synaptic organization, and synaptic signaling genes, indicative of synaptic immaturity or synaptogenic delay due to CHD8 loss of function.

In radial glia of the early embryonic cortex, genes associated with risk for neurodevelopmental disorders and genes involved in chromatin remodeling, neuron projection development, and migration were downregulated.

CHD8 loss of function had cell-type-biased impacts in the developing mouse cortex, which were dynamic across development. There were distinct signatures in early radial glia, the primary progenitor cell type of the cortex, and in maturing excitatory neurons.

We found that Chd8 and other ASD risk-associated genes had convergent expression patterns that were conserved between the mouse and human developing cortex, with expression peaking in differentiating neurons.

We developed a mouse model of CHD8 loss of function and performed the first published single-cell transcriptomics analysis of the impacts of CHD8 loss of function across mouse cortical development.

Loss-of-function variants in CHD8 are strongly associated with risk of autism spectrum disorder (ASD) and macrocephaly. Previous studies, including work from our lab, implicated CHD8 in broad gene regulation during neurodevelopment, including the direct regulation of other ASD risk-associated genes.

Great article, Caleb! Thanks for writing about our work.

It's now part of an art installation on beauty in science, outside of the Yale Med School library. Here's Je Won showing her work: