Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development.

Scientists studied mice with mutations in the Chd8 gene, which is linked to autism risk. They found that this gene mutation affects brain development differently at different stages. In early development, it disrupts genes important for brain cell growth. Later in development, it affects genes needed for brain cells to connect properly. This research helps explain how certain genetic changes might contribute to autism by interfering with normal brain development.

This preclinical study investigated how Chd8 gene mutations, associated with autism risk, affect brain development in mice. Using advanced single-cell sequencing, researchers examined gene expression changes in developing cortical brain regions. The study found that Chd8 haploinsufficiency (having only one functional copy) caused distinct patterns of gene dysregulation at different developmental stages. In embryonic brain stem cells (radial glia), genes involved in brain development and chromatin remodeling were disrupted.

In postnatal excitatory neurons, genes related to synaptic function and organization were affected, suggesting impaired synapse formation. The research revealed that Chd8 and other autism-associated genes follow similar expression patterns in both mouse and human brain development, providing insights into potential mechanisms underlying autism spectrum disorder.

These findings advance understanding of how CHD8 mutations contribute to autism by disrupting specific developmental processes. The research suggests that therapeutic interventions may need to target different mechanisms at different developmental stages, though clinical applications remain distant given the preclinical nature of this work.

This is a preclinical mouse study, so findings may not directly translate to humans. Sample size not reported. The study focuses on cortical development only and may not capture effects in other brain regions relevant to autism.

Disruptive variants in the chromodomain helicase CHD8 are associated with risk for autism spectrum disorder (ASD). CHD8 haploinsufficiency is hypothesized to contribute to ASD by perturbing neurodevelopmental gene expression. However, insight into cell-type-specific transcriptional effects of CHD8 haploinsufficiency remains limited. We used single-cell and single-nucleus RNA sequencing to identify dysregulated genes in the embryonic and juvenile Chd8mouse cortex.

Chd8 and other ASD risk-associated genes showed a convergent expression trajectory conserved between mouse and human developing cortex, increasing from progenitor zones to the cortical plate. Genes associated with neurodevelopmental disorders or involved in chromatin remodeling and neuron projection development were dysregulated in Chd8embryonic radial glia. Genes implicated in synaptic activity and organization were dysregulated in Chd8postnatal excitatory cortical neurons, suggesting impaired synaptogenesis. Our findings reveal complex patterns of transcriptional dysregulation due to Chd8 haploinsufficiency, potentially with distinct impacts on progenitors and maturing neurons in the excitatory neuronal lineage.