scRNA-Sequencing uncovers a TCF-4-dependent transcription factor network regulating commissure development

Abstract

Intercortical connectivity is important for higher cognitive brain functions by providing the basis for integrating information from both hemispheres. We show that ablation of the neurodevelopmental disorder associated bHLH factor Tcf4 results in complete loss of forebrain commissural systems in mice. Applying a new bioinformatic strategy integrating transcription factor expression levels and regulon activities from single cell RNA-sequencing data predicted a TCF-4 interacting transcription factor network in intercortical projection neurons regulating commissure formation. This network comprises a number of regulators previously linked to the pathogenesis of intellectual disability, autism-spectrum disorders and schizophrenia, e.g. Foxg1, Sox11 and Brg1. Furthermore, we demonstrate that TCF-4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implied in this process. Our study provides a regulatory transcriptional network for the development of interhemispheric connectivity with potential pathophysiological relevance in neurodevelopmental disorders.