Species-specific basal fluidization shapes early forebrain development

Abstract The human forebrain exhibits an expanded surface area compared with other great apes. Despite progress in dissecting species-specific gene expression programs and cell lineages, the tissue-level physical mechanisms underlying human-specific neurodevelopment remain unclear. Here, by quantifying tissue dynamics and mechanics using oil microdroplets in cerebral organoids from humans, gorillas, chimpanzees, and mice, we uncover a transient tissue fluidization occurring exclusively in the basal region of human neuroepithelia. Enhanced droplet motility and frequent cell rearrangements reveal this basal fluidization, which gradually diminishes at the onset of neurogenesis in humans. By contrast, such basal fluidization is not detected in non-human neuroepithelia examined here. Mechanistically, basal fluidization is driven by basal nuclear fluctuations and facilitated by expanded intercellular spaces. Increasing N-cadherin expression in human neuroepithelia to gorilla levels suppresses both nuclear fluctuations and basal fluidization. Integrating simulations of neuroepithelial dynamics with experimental data, we further find that nuclear fluctuations underlying basal fluidization promote the insertion of newly divided nuclei into the basal side to support tangential surface expansion, a hallmark of human forebrain development.