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Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions

  • Jessenya Mil1
  • Jose A. Soto1
  • Abigail S. Krall1
  • Julia Peloggia1
  • Sara Frigui1
  • Olivia S. Fong1
  • Laila Sathe2
  • Nedas Matulionis1
  • Francesca Day1
  • Linsey Stiles3
  • Katrina P. Montales2
  • Daria J. Azizad1
15 more authors
  • Carlos E. Gonzalez1
  • Elisa Fazzari1
  • Matthew X. Li1
  • Patricia R. Nano1
  • Antoni Andreu Martija1
  • Cesar A. Perez-Ramirez1
  • Claudia V. Nguyen1
  • Brittney D Wick4
  • Weihong Ge1
  • Ryan L. Kan1
  • Madeline G. Andrews5
  • Maximilian Haeussler4
  • Michael F. Wells6
  • Heather R. Christofk7
  • Aparna Bhaduri8
8 affiliations
  1. 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  2. 2Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  3. 3Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
  4. 4Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
  5. 5School of Biological and Health Systems Engineering, Arizona State University, Phoenix, AZ, USA
  6. 6Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
  7. 7Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected]
  8. 8Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected]
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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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Cite

BibTeXRIS
BibTeX
@article{mil2026metabolic,
  title = {{Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions}},
  author = {Jessenya Mil and Jose A. Soto and Abigail S. Krall and Julia Peloggia and Sara Frigui and Olivia S. Fong and Laila Sathe and Nedas Matulionis and Francesca Day and Linsey Stiles and Katrina P. Montales and Daria J. Azizad and Carlos E. Gonzalez and Elisa Fazzari and Matthew X. Li and Patricia R. Nano and Antoni Andreu Martija and Cesar A. Perez-Ramirez and Claudia V. Nguyen and Brittney D Wick and Weihong Ge and Ryan L. Kan and Madeline G. Andrews and Maximilian Haeussler and Michael F. Wells and Heather R. Christofk and Aparna Bhaduri},
  journal = {Cell},
  year = {2026},
  month = aug,
  doi = {10.1016/j.cell.2026.07.023},
  url = {https://doi.org/10.1016/j.cell.2026.07.023},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions
AU  - Jessenya Mil
AU  - Jose A. Soto
AU  - Abigail S. Krall
AU  - Julia Peloggia
AU  - Sara Frigui
AU  - Olivia S. Fong
AU  - Laila Sathe
AU  - Nedas Matulionis
AU  - Francesca Day
AU  - Linsey Stiles
AU  - Katrina P. Montales
AU  - Daria J. Azizad
AU  - Carlos E. Gonzalez
AU  - Elisa Fazzari
AU  - Matthew X. Li
AU  - Patricia R. Nano
AU  - Antoni Andreu Martija
AU  - Cesar A. Perez-Ramirez
AU  - Claudia V. Nguyen
AU  - Brittney D Wick
AU  - Weihong Ge
AU  - Ryan L. Kan
AU  - Madeline G. Andrews
AU  - Maximilian Haeussler
AU  - Michael F. Wells
AU  - Heather R. Christofk
AU  - Aparna Bhaduri
PY  - 2026
DA  - 2026/08/04
JO  - Cell
DO  - 10.1016/j.cell.2026.07.023
UR  - https://doi.org/10.1016/j.cell.2026.07.023
AB  - 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.
SN  - 0092-8674
SN  - 1097-4172
ER  -