Mechanical constraints regulate embryonic stem cell mitosis in the developing brain

Research on mitosis has predominantly examined cell-autonomous mechanisms, yet its regulation and consequences within the broader physiological context remain largely unexplored. It remains, therefore, unknown whether and how spindle assembly and chromosome segregation are influenced by tissue properties. We have investigated this question in the mammalian embryonic brain, using high-resolution microscopy combined with pharmacological perturbations and minimal cell systems to break down the contribution of tissue environment to mitotic fidelity. We found that cell density imposes biomechanical constraints upon the apical radial glial (aRG) cell population during their highly proliferative period, which enhances spindle pole microtubule polymerization rates and potentiates chromosome mis-segregation. Mechanistically, we show that cortical tension relying on branched actin organization at the cell cortex conveys mechanical stress exerted by cell density. We identified the microtubule depolymerase MCAK/Kif2C as a critical effector downstream of cortical actin, linking actin dynamics to spindle pole activity. Altogether, our findings demonstrate that aRG are mechanosensitive during their expansion phase, and that excessive biomechanical stress, imposed by high cell density in developing tissues, can disrupt mitotic fidelity.