Molecular Identity of Human Outer Radial Glia during Cortical Development
Open accessAbstract
Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.
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Radial glia share transcriptomic similarities with mature astrocytes and are progenitor cells that give rise to numerous distinct cell fates, including neuronal cells, astrocytes, oligodendrocytes, and ependymal cells.
“Radial glia, which share transcriptomic similarities with mature astrocytes, are progenitor cells that give rise to numerous distinct cell fates, including neuronal cells, astrocytes, oligodendrocytes, and ependymal cells.34,35”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [34]
The Results section, “Extensive Neurogenic Capacity of oRG Cells” (page unavailable), reports that outer radial glia share some genes with later astrocytes and that single cells produced neuronal and glial daughters. It does not establish broad transcriptomic similarity to mature astrocytes or identify astrocytes, oligodendrocytes, and ependymal cells as distinct daughter-cell fates. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAfter the molecular identity of oRGs was established, an OSVZ-like zone containing oRGs could be reliably identified based on marker expression.
“It was only after the molecular identity of oRGs was established48 that an OSVZ-like zone containing oRGs could be reliably identified based on marker expression5 (FIG. 1).”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [48]
Cells in a given spatial position may be more quiescent, complicating inference of whether variation should be attributed to cell cycle or spatial position.
“For instance, cells in a given position may be more quiescent compared to other positions, which complicates the inference of the biological variation that should be attributed to cell cycle versus spatial position101.”
From Revealing the vectors of cellular identity with single-cell genomics (2016) · cites this paper as [101]
scLVM has been effectively used to handle the cell cycle as a known covariate.
“scLVM101, a statistical framework developed to account for unwanted and a priori known covariates from scRNA-seq data, has been effectively used to handle the cell cycle as a known covariate.”
From Revealing the vectors of cellular identity with single-cell genomics (2016) · cites this paper as [101]
Large variation induced by the cell cycle in some scRNA-seq experiments may conceal other important biological variation, especially differentiation.
“Thus, the large variation induced by the cell cycle in some scRNA-seq experiments may conceal other important sources of biological variation101, especially cellular differentiation processes137,141,151,152.”
From Revealing the vectors of cellular identity with single-cell genomics (2016) · cites this paper as [101]
In TH2 differentiation, scLVM highlighted correlated genes enriched in TH2 differentiation and distinguished two subpopulations that were not detectable when cell cycle covariates were present.
“Applied to T helper 2 (TH2) cell differentiation, scLVM helped highlight a set of correlated genes enriched in TH2 cell differentiation and distinguish two subpopulations—neither of which is detectable when the cell cycle covariates are present101.”
From Revealing the vectors of cellular identity with single-cell genomics (2016) · cites this paper as [101]
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“These progenitors appear later in development than the ventricular radial glia and are characterized by the lack of an apical process 62,63 .”
Linking mitochondria metabolism, developmental timing, and human brain evolution
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- Authors
- Pollen, A. A., Nowakowski, T. J., Chen, J., Retallack, H., Sandoval-Espinosa, C., Nicholas, C. R., Shuga, J., Liu, S. J., Oldham, M. C., Diaz, A., Lim, D. A., Leyrat, A. A., West, J. A., & Kriegstein, A. R.
- Affiliations
- University of California, San Francisco (US)
- Standard BioTools (United States) (US)
- Corresponding author
- Pollen, Alex A.
- Kriegstein, Arnold R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 163
- Issue
- 1
- Pages
- 55-67
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4583716
- OpenAlex
- W2166643977
- Cited by
- 908
- References
- 65
- Citations by year
- 2026: 68 · 2025: 73 · 2024: 84 · 2023: 96 · 2022: 86 · 2021: 106 · 2020: 111 · 2019: 87 · 2018: 87 · 2017: 54 · 2016: 52 · 2015: 3
- FWCI
- 26.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health (UL1TR000004)
- University of California, San Francisco
- National Institute of Mental Health (U01MH105989)
- National Institute of General Medical Sciences (T32GM007618)
- National Institute of Neurological Disorders and Stroke (R01NS075998)
- NIH Blueprint for Neuroscience Research
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- outer radial glia, human neocortex development, outer subventricular zone, single-cell gene expression, extracellular matrix, cell migration, stemness genes, STAT3 signaling, cell cycle progression, self-renewal, growth factor signaling, TNC, PTPRZ1, HOPX, LIFR, clonal analysis, human brain evolution
- MeSH terms
- Animals, Cell Cycle, Humans, Macaca, Neuroglia, Signal Transduction, Neocortex, STAT3 Transcription Factor, Mice, Stem Cell Niche, Neurogenesis, Neural Stem Cells, Single-Cell Analysis
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