Transcription factor 4 regulates the interhemispheric midline remodeling through neuron–astroglia communications during corpus callosum formation

Agenesis of the corpus callosum (CC), the largest axon tract bridging the two hemispheres of the brain to support higher cognitive functions, is linked to various neurological disorders, including intellectual disability and autism spectrum disorders. Mutations of the transcription factor 4 (TCF4) cause Pitt-Hopkins Syndrome (PTHS), an autism spectrum brain disorder characterized by severe intellectual disability. Through ex vivo transplantation assays and single-cell RNA sequencing of the interhemispheric midline, we found that Tcf4-mediated neuron-astroglia communication is essential for establishing the midline structure and subsequent CC formation. Conditional inactivation of Tcf4 in guidepost neurons disrupts astroglia functions and impedes interhemispheric fissure closure, thereby preventing axonal crossing of callosal projection neurons to the contralateral cortex. Moreover, we identified Sema7a as a key mediator of neuron-astroglia communications. Therefore, our study reveals a crucial role of cell-cell communication in interhemispheric midline remodeling, providing insights into the potential mechanisms underlying TCF4 associated neurological disorders.