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

## TL;DR

The study shows that cortical tension acts as a mechanical barrier to prevent premature neuron formation, and its regulation could help in modeling brain diseases.

## Contribution

The paper introduces cortical tension as a mechano-checkpoint that interacts with genetic programs during neurogenesis.

## Key findings

- Deleting Plexin-B2 lowers cortical tension, leading to premature neuronal differentiation.
- Cortical tension and epigenetic barriers work together to control developmental timing.
- Plexin-B2 ablation in organoids caused progenitor depletion and disorganization, similar to human disease.

## 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.