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Updated: Jan 5, 2026
Electroporation of Sliced Human Cortical Organoids for Studies of Gene Function
Published on: November 29, 2024
Human Cortical Organoids Expose a Differential Function of GSK3 on Cortical Neurogenesis
Alejandro López-Tobón1, Carlo Emanuele Villa2, Cristina Cheroni1
1Laboratory of Stem Cell Epigenetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
Abstract:
The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture.
Insights
Glycogen synthase kinase 3 (GSK3) inhibition in human brain organoids boosted neural progenitor proliferation but disrupted cortical development. GSK3 uniquely regulates glutamatergic lineages and outer radial glia.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Neural progenitor proliferation and polarity are critical for brain cortex development.
- Glycogen synthase kinase 3 (GSK3) is implicated in regulating these processes in animal models.
- The role of GSK3 in human corticogenesis is not fully understood.
Purpose of the Study:
- To investigate the longitudinal effects of GSK3 inhibition on human corticogenesis.
- To elucidate the specific roles of GSK3 signaling in human neural progenitor behavior and lineage specification.
Main Methods:
- Utilized human cortical brain organoids for in vitro studies.
- Applied chronic GSK3 inhibition across multiple developmental stages.
- Employed single-cell transcriptome profiling to analyze molecular changes.
Main Results:
- GSK3 inhibition led to increased neural progenitor proliferation.
- Disruption of cortical tissue architecture was observed with chronic GSK3 inhibition.
- Single-cell profiling revealed GSK3's selective role in glutamatergic lineages and outer radial glia output.
- Identified a robust GSK3-dependent transcriptional network governing neuronal identity.
Conclusions:
- GSK3 plays a crucial, selective role in regulating human corticogenesis, particularly in glutamatergic neurogenesis.
- While GSK3 impacts tissue architecture, core programs of neuronal identity remain robust.
- Human brain organoids provide a valuable model for studying developmental neurobiology and the impact of signaling pathways.
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