Genetic disruption of gene-regulatory proteins has emerged as a major underlying cause of autism and related neurodevelopmental disorders (ASD/NDD). Precise gene regulation is essential for orchestrating neurogenesis, migration and cell specification in early nervous system development, but it is also critical to maintain cell function in mature circuits. Thus, a major challenge in understanding the etiology of ASD/NDD caused by mutation of gene-regulatory proteins is to determine when and how the cellular makeup and anatomy of the brain is altered during early development, while integrating these effects with the ongoing functional impact of altered transcription in mature circuits.

Classically, experimental approaches have not been able to simultaneously assess cellular anatomy and transcriptomic disruption in models of ASD/NDD. The recent emergence of spatial transcriptomic methods provides an exciting new opportunity to assess gene expression in the context of intact anatomy in the brain at unprecedented resolution, but these approaches have not yet been widely utilized in the study of ASD/NDD.

In the current project, Harrison Gabel and colleagues plan to combine spatial transcriptomic technologies with innovative neuron projection labeling and sample preparation methods to phenotype three models of ASD/NDD in which neuronal DNA methylation and gene regulation is disrupted (MeCP2, DNMT3A and NSD1). His team’s analysis will define overlapping and distinct effects on cellular composition across brain regions in these models while simultaneously exploring convergent transcriptomic dysregulation associated with specific neuronal subtypes and projection targets. These studies will provide insight into shared and distinct cellular and molecular disruptions across DNA methylation-associated ASD/NDDs and establish spatial transcriptomics as a powerful paradigm for integrated anatomical and gene regulatory phenotyping in the study of neurodevelopmental disorders.