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

Mil, J.; Soto, J. A.; Matulionis, N.; Krall, A.; Day, F.; Stiles, L.; Montales, K. P.; Azizad, D. J.; Gonzalez, C. E.; Nano, P. R.; Martija, A. A.; Perez-Ramirez, C. A.; Nguyen, C. V.; Kan, R. L.; Andrews, M. G.; Christofk, H. A.; Bhaduri, A.

doi:10.1101/2025.03.10.642470

bioRxiv · 10.1101/2025.03.10.642470

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

Mil, J.·Soto, J. A.·Matulionis, N.·Krall, A.·Day, F.·Stiles, L.·Montales, K. P.·Azizad, D. J.·Gonzalez, C. E.·Nano, P. R.·Martija, A. A.·Perez-Ramirez, C. A.·Nguyen, C. V.·Kan, R. L.·Andrews, M. G.·Christofk, H. A.·Bhaduri, A.

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Abstract

Characterization of cell type emergence during human cortical development, which enables unique human cognition, has focused primarily on anatomical and transcriptional characterizations. Metabolic processes in the human brain that allow for rapid expansion, but contribute to vulnerability to neurodevelopmental disorders, remain largely unexplored. We performed a variety of metabolic assays in primary tissue and stem cell derived cortical organoids and observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis during late neurogenesis. By depleting glucose levels in cortical organoids, we increased outer radial glia, astrocytes, and inhibitory neurons. We found the pentose phosphate pathway (PPP) was impacted in these experiments and leveraged pharmacological and genetic manipulations to recapitulate these radial glia cell fate changes. These data identify a new 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.

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Mil, J., Soto, J. A., Matulionis, N., Krall, A., Day, F., Stiles, L., Montales, K. P., Azizad, D. J., Gonzalez, C. E., Nano, P. R., Martija, A. A., Perez-Ramirez, C. A., Nguyen, C. V., Kan, R. L., Andrews, M. G., Christofk, H. A., Bhaduri, A.. 2025-03-11. Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions. https://doi.org/10.1101/2025.03.10.642470

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