Temporal regulation of progenitor lineage progression and output by NFIs underlying human neocortical malformation

Nuclear factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here, we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), thereby bidirectionally controlling neocortical development. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression-level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and cortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental-stage-dependent precocious production of diverse neural progenies. Moreover, NFIs exhibit positive autoregulation and progressive increase in expression and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development.