FGF-MAPK signaling regulates human deep-layer corticogenesis

Summary Despite heterogeneity across the six layers of the mammalian cortex, all excitatory neurons are generated from a single founder population of neuroepithelial stem cells. However, how these progenitors alter their layer competence over time remains unknown. Here, we used human embryonic stem cell-derived cortical progenitors to examine the role of fibroblast growth factor (FGF) and Notch signaling in influencing cell fate, assessing their impact on progenitor phenotype, cell-cycle kinetics, and layer specificity. Forced early cell-cycle exit, via Notch inhibition, caused rapid, near-exclusive generation of deep-layer VI neurons. In contrast, prolonged FGF2 promoted proliferation and maintained progenitor identity, delaying laminar progression via MAPK-dependent mechanisms. Inhibiting MAPK extended cell-cycle length and led to generation of layer-V CTIP2+ neurons by repressing alternative laminar fates. Taken together, FGF/MAPK regulates the proliferative/neurogenic balance in deep-layer corticogenesis and provides a resource for generating layer-specific neurons for studying development and disease.
Highlights • FGF/MAPK regulates the proliferative/neurogenic balance in deep-layer corticogenesis • FGF/MAPK signaling maintains the progenitor pool and generates layer-VI neurons • MAPK inhibition prolongs cell cycle to yield layer-V neurons, repressing other fates • Protocols to generate layer-specific cortical neurons to study development and disease
Despite heterogeneity across human cortical layers, all excitatory neurons evolve from a single founder stem cell population. How these progenitors alter layer competence over time is unknown. Using human pluripotent stem cell-derived cortical progenitors, we demonstrate that FGF/MAPK signaling regulates the proliferative/neurogenic balance in deep-layer corticogenesis. Modulating FGF/MAPK enables generation of layer-specific neurons to study development and disease.