Mutations in genes involved in mitosis are frequently found in primary microcephaly (MCPH), a condition characterized by reduced brain size at birth. Interestingly, many of these mutations specifically affect brain development, without impacting other organs or overall body growth. To investigate the origins of this selective vulnerability in neural stem cells during development, we employ a range of model systems, including mice, patient-derived fibroblasts, and iPSC-derived neuronal rosettes. Using a combination of high-resolution microscopy, cell pattern analysis, and acute cytoskeleton perturbations, our work reveals a mechanism that may underlie the heightened sensitivity of neural stem cells to chromosome mis-segregation.