Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions

Cortical development involves rapid progenitor expansion and cell diversification that is likely supported by tightly regulated metabolic programs, yet these programs, particularly in human development remain largely uncharacterized. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. Across developmental stages, we observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered progenitor and neuronal composition, increasing outer radial glia and inhibitory neurons populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes and promoted radial glial maturation. Ribose was sufficient to rescue the radial glia gene expression changes, revert organoid cell type composition, and restore the levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating radial glia cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.