Post-translational Tuning of Human Cortical Progenitor Neuronal Output

The striking expansion of the human neocortex is driven by the ability of radial glial cells (RGCs) to prolong neurogenesis without exhausting their progenitor pool, thereby producing more neurons, particularly in the upper layers. The mechanisms underlying enhanced human neurogenic output remain unresolved. We hypothesized that post-translational modification of conserved proteins could provide a flexible mechanism supporting species-specific patterns of neurogenesis. Here, we identify phosphorylation of the proneural factor NEUROGENIN2 as a regulator of human RGC neuronal output by modulating its pioneering-like activity, at the expense of its transactivation function. This, in turn, remodels the RGC chromatin landscape, resulting in a forward temporal shift of RGC gene regulatory networks and leading to increased neuronal production biased towards upper-layer neurons. Our work proposes a conceptual framework for how subtle modifications of conserved processes, and not just new genes, encode tunable mechanisms for species-specific trajectories of brain development.