ARID1B controls transcriptional programs of axon projection in the human corpus callosum

Abstract

AbstractMutations inARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC). This condition is characterized by a partial or complete absence of the corpus callosum (CC), an interhemispheric white matter tract that connects distant cortical regions. Using human neural organoids, we identify a vulnerability of callosal projection neurons (CPNs) toARID1Bhaploinsufficiency, resulting in abnormal maturation trajectories and dysregulation of transcriptional programs of CC development. Through a novelin vitromodel of the CC tract, we demonstrate thatARID1Bmutations reduce the proportion of CPNs capable of forming long-range projections, leading to structural underconnectivity phenotypes. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous defects in axonogenesis as a cause of ACC in ARID1B patients.Abstract FigureGraphical abstractHuman callosal projection neurons are vulnerable toARID1Bhaploinsufficiency.(Top)During healthy development, callosal projection neurons (CPNs) project long interhemispheric axons, forming the corpus callosum (CC) tract, which can be modeledin vitro.(Bottom)In ARID1B patients, transcriptional dysregulation of genetic programs of CC development reduces the formation of long-range projections from CPNs, causing CC agenesisin vivoand underconnectivity phenotypesin vitro.