Human organoid screen links transient translational modulation to progenitor progression in corticogenesis
- 1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros
Abstract
Human pluripotent stem cell-derived models are increasingly used to recapitulate aspects of human corticogenesis, including the emergence of diverse cortical cell types and their progression through developmental states. These systems offer an opportunity to dissect the molecular mechanisms regulating transitions between cell states, but methods for perturbing them systematically at scale remain limited. Here, we developed a semi-automated culture and high-throughput arrayed screening platform for human cortical organoids. Using a library of 1,280 small molecules designed to systematically target major signaling and regulatory pathways, we screened for modulators of EOMES, which encodes for the transcription factor TBR2, and identified Emetine, an inhibitor of translation elongation, as the top hit. The effect of Emetine on cortical cell-state progression was reproduced across human pluripotent stem cell lines, non-human primate cortical organoids, and primary human cortical tissue but not broadly across translation inhibitors. Moreover, transient exposure resulted in a shift from dividing radial glia towards cortical glutamatergic neurons. Mechanistically, nascent-proteome profiling revealed an early and coordinated remodeling of newly translated proteins that preceded detectable transcriptional changes, placing translational regulation upstream of the ensuing cell-state transition. Together, these findings highlight a role for specific translational inhibitors in promoting cortical cell-state progression and establish a scalable platform for systematic perturbation and discovery in human neural organoids.
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BibTeX
@misc{avar2026human,
title = {{Human organoid screen links transient translational modulation to progenitor progression in corticogenesis}},
author = {M. Avar and T. C. Lantz and D. Heinzer and M. M. Onesto and K. Imaizumi and V. Kulur and M. A. Fonseca and S. Yoon and C. Dong and B. J. Levy and M.-Y. Li and E. Sosa and A. Bermudez and D. Wood and I. Liu and A. Clark and A. Brunet and S. Pitteri and K. Kelley and M. Barna and S. P. Pasca},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764664},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764664v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Human organoid screen links transient translational modulation to progenitor progression in corticogenesis
AU - M. Avar
AU - T. C. Lantz
AU - D. Heinzer
AU - M. M. Onesto
AU - K. Imaizumi
AU - V. Kulur
AU - M. A. Fonseca
AU - S. Yoon
AU - C. Dong
AU - B. J. Levy
AU - M.-Y. Li
AU - E. Sosa
AU - A. Bermudez
AU - D. Wood
AU - I. Liu
AU - A. Clark
AU - A. Brunet
AU - S. Pitteri
AU - K. Kelley
AU - M. Barna
AU - S. P. Pasca
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764664
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764664v1
AB - Human pluripotent stem cell-derived models are increasingly used to recapitulate aspects of human corticogenesis, including the emergence of diverse cortical cell types and their progression through developmental states. These systems offer an opportunity to dissect the molecular mechanisms regulating transitions between cell states, but methods for perturbing them systematically at scale remain limited. Here, we developed a semi-automated culture and high-throughput arrayed screening platform for human cortical organoids. Using a library of 1,280 small molecules designed to systematically target major signaling and regulatory pathways, we screened for modulators of EOMES, which encodes for the transcription factor TBR2, and identified Emetine, an inhibitor of translation elongation, as the top hit. The effect of Emetine on cortical cell-state progression was reproduced across human pluripotent stem cell lines, non-human primate cortical organoids, and primary human cortical tissue but not broadly across translation inhibitors. Moreover, transient exposure resulted in a shift from dividing radial glia towards cortical glutamatergic neurons. Mechanistically, nascent-proteome profiling revealed an early and coordinated remodeling of newly translated proteins that preceded detectable transcriptional changes, placing translational regulation upstream of the ensuing cell-state transition. Together, these findings highlight a role for specific translational inhibitors in promoting cortical cell-state progression and establish a scalable platform for systematic perturbation and discovery in human neural organoids.
ER -