Cortical tension as a mechanical barrier to safeguard against premature differentiation during neurogenesis

Abstract

Neuronal differentiation requires coordinated gene reprogramming and morphodynamic remodeling. How mechanical forces integrate with nuclear gene programs during neurogenesis remains unresolved. Here, we identify cortical tension as a mechanical barrier that safeguards against premature neuronal differentiation. Deletion of Plexin-B2, a guidance receptor controlling actomyosin contractility, lowers this barrier, enabling neurite outgrowth and accelerating neuronal lineage commitment. We show that coupling of extrinsic differentiation cues with intrinsic morphodynamics is essential for stabilizing neuronal fate and that cortical barrier and epigenetic barrier act in concert to regulate developmental timing. In cerebral organoids, Plexin-B2 ablation triggered premature cell-cycle exit and differentiation, resulting in progenitor pool depletion and neuroepithelial disorganization, phenotypes echoing intellectual disability in patients with rare pathogenic PLXNB2 variants. Our studies demonstrate that cortical tension functions as mechano-checkpoint that regulates the onset of neurogenesis. Lowering this barrier may provide a strategy to accelerate induced neuron generation and maturation for CNS disease modeling.