Cortical Interlaminar Astrocytes Are Generated Prenatally, Mature Postnatally, and Express Unique Markers in Human and Nonhuman Primates
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Interlaminar astrocytes (ILAs) are a subset of cortical astrocytes that reside in layer I, express GFAP, have a soma contacting the pia, and contain long interlaminar processes that extend through several cortical layers. We studied the prenatal and postnatal development of ILAs in three species of primates (rhesus macaque, chimpanzee, and human). We found that ILAs are generated prenatally likely from radial glial (RG) cells, that ILAs proliferate locally during gestation, and that ILAs extend interlaminar processes during postnatal stages of development. We showed that the density and morphological complexity of ILAs increase with age, and that ILAs express multiple markers that are expressed by RG cells (Pax6, Sox2, and Nestin), specific to inner and outer RG cells (Cryab and Hopx), and astrocyte markers (S100β, Aqp4, and GLAST) in prenatal stages and in adult. Finally, we demonstrated that rudimentary ILAs in mouse also express the RG markers Pax6, Sox2, and Nestin, but do not express S100β, Cryab, or Hopx, and that the density and morphological complexity of ILAs differ between primate species and mouse. Together these findings contribute new information on astrogenesis of this unique class of cells and suggest a lineal relationship between RG cells and ILAs.
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Early ILAs can locally proliferate until the late second trimester and increase in complexity during the postnatal period.
“These early ILAs can locally proliferate (as indicated by positivity for Ki67, a mitotic marker) until the late second trimester and increase in complexity during the postnatal period”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Falcone et al., 2021
The ‘ILAs proliferate locally at the final destination’ section reports Ki67-positive ILAs prenatally, and the postnatal-development section reports increasing morphological complexity. But the paper also reports Ki67-positive ILAs at GD109 and GD123, both identified as third-trimester ages, so ‘until the late second trimester’ does not accurately describe the reported timing. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNewborn ILA somata positive to GFAP and S100β in contact with the pia mater are present during early prenatal stages in rhesus macaque and humans.
“Falcone et al. (2021), showed the presence of newborn ILA somata (positive to GFAP and S100β) in contact with the pia mater during early prenatal stages in rhesus macaque and humans.”
From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Falcone et al., 2021
In “ILAs have a prenatal origin in primates” (page unavailable), the paper reports S100β-positive cells resembling ILAs whose somata contact the pia in GD109 rhesus macaque and GW21 human tissue. It does not establish that those cells were newborn or positive for both GFAP and S100β. The same section cautions that GFAP-positive fibers at earlier prenatal stages could be radial glial fibers rather than ILAs. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAstro-TE cluster 5219 is located at the pia of telencephalon and has high expression of Gfap, consistent with the definition of interlaminar astrocytes (ILAs).
“Astro-TE cluster 5219 is located at the pia of telencephalon (Fig. 4b) and has high expression of Gfap (Extended Data Fig. 11e), consistent with the definition of interlaminar astrocytes (ILAs)73.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [73]
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“Importantly, Pax6 is also expressed in glial progenitors in the adult brain [66,67].”
BackgroundEvaluation of advances in cortical development using model systems
Nano, P. R., & Bhaduri, A. (2022) · Developmental Neurobiology · doi:10.1002/dneu.22879 · Cited by 8 · see citing works
The role of astrocytes in human Huntington's disease pathology
Al‐Dalahmah, O., & Goldman, J. E. (2025) · Journal of Huntington s Disease · doi:10.1177/18796397251344173 · Cited by 6 · see citing works
“44 Interlaminar and fi brous astrocytes, but not proto-plasmic astrocytes, express the cell membrane matrix receptor CD44.”
InfluentialShaping the Neocortex: Radial Glia and Astrocytes in Development and Evolution
Mosti, F., Kawasaki, H., Babbitt, C. C., Benedetto, B. D., Silver, D. L., Kalebic, N., & Falcone, C. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.1301-25.2025 · Cited by 5 · see citing works
Self-citationRevealing heterogeneity and damage response in the adult human utricle
Luca, E., Ibeh, N., Yamamoto, R., Liang, W., Bennett, D., Lin, V., Chen, J., Lovett, M., & Dabdoub, A. (2025) · Nature Communications · doi:10.1038/s41467-025-66358-8 · Cited by 5 · see citing works
“CRYAB is a stem/progenitor cell marker involved in regeneration of human interlaminar astrocytes 38 and induces osteogenesis differentiation of human bone marrow stem cells, stabilizing β -catenin and promoting Wnt signalling 39 .”
Scaled Complexity of Mammalian Astrocytes: Insights From Mouse and Macaque
Heffernan, K. S., Martinez, I., Jaeger, D., Khakh, B. S., Smith, Y., & Galván, A. (2024) · The Journal of Comparative Neurology · doi:10.1002/cne.25665 · Cited by 5 · see citing works
“We chose Layer 5 to avoid Layer 1 interlaminar astrocyte processes which traverse Layers 2–4 in rhesus macaque (Falcone, Penna, et al. 2021).”
Zhou, N., Fan, Z., Tong, Y., Xiao, X., Xie, Y., Qi, Z., & Chen, L. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12913 · Cited by 5 · see citing works
“They further described rudimentary ILA that have short GFAP+ processes that do not exit layer I and ‘typical’ ILA with longer GFAP+ processes that exit layer I [19, 31].”
BackgroundDoes Perinatal Intermittent Hypoxia Affect Cerebrovascular Network Development?
Coelho‐Santos, V., Cruz, A.-J. N., & Shih, A. Y. (2023) · Developmental Neuroscience · doi:10.1159/000530957 · Cited by 5 · see citing works
Verkhratsky, A., & Butt, A. M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821565-4.00009-2 · Cited by 4 · see citing works
Bretová, K., Svobodová, V., & Dubový, P. (2022) · Histochemistry and Cell Biology · doi:10.1007/s00418-022-02161-6 · Cited by 4 · see citing works
Metabolism Controls the Timing of Human Brain Development and Maturation
Rava, V., Cannone, E., Francolini, M., & Taverna, E. (2026) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70180 · Cited by 3 · see citing works
Special characteristics of human astrocytes and their roles in brain homeostasis
Kousa, I., Talvio, K., Peteri, U., & Castrén, M. L. (2026) · Neuroscience Applied · doi:10.1016/j.nsa.2026.107000 · Cited by 3 · see citing works
“Most astrocytes are generated between GW23 – 26, although astrocyte maturation continues postnatally (Roessmann and Gambetti, 1986; Falcone et al., 2021; Zhong et al., 2018).”
InfluentialVerma, R., Jayakumar, J., Folkerth, R. D., Manger, P. R., Bota, M., Majumder, M., Pandurangan, K., Savoia, S., Karthik, S., Kumarasami, R., et al. (2024) · The Journal of Comparative Neurology · doi:10.1002/cne.25612 · Cited by 3 · see citing works
A brief sketch across multiscale and comparative neuroanatomical features
Rockland, K. S. (2023) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2023.1108363 · Cited by 2 · see citing works
“In contrast with the relatively subtle morphological differences in neurons, pronounced structural differentiations have been identified for glia; namely, humans have larger and structurally more complex protoplasmic and fibrous astrocytes, and several distinct glia subclasses not so far identified in rodents (Oberhei…”
ResultNeuron-Astrocyte Interactions: A Human Perspective
Pio, T., Hill, E. J., Kebede, N., Andersen, J., & Sloan, S. A. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-64839-7_4 · Cited by 2 · see citing works
Tyurikova, O. (2024) · Regenerative medicine reports . · doi:10.4103/regenmed.regenmed-d-24-00003 · Cited by 2 · see citing works
“16 Throughout postnatal development, ILAs increase in density and process complexity and express markers characteristic of stem cells and astrocytes.”
InfluentialKavakli, E., Gul, N., Begentas, O. C., & Kiris, E. (2025) · Advances in experimental medicine and biology · doi:10.1007/5584_2024_840 · Cited by 1 · see citing works
Ferreira, G. A. M., & Pinto, L. (2025) · Glia · doi:10.1002/glia.70031 · Cited by 2 · see citing works
“In some cases, collection of gestational tissue provides further insights into the process (Falcone et al. 2021; Yang et al. 2022; Zhou et al. 2022).”
Arzola, E. P., Yu, G., Xiong, L., Lee, D., Wu, A., Paruchuri, S., Skinner, J., Wang, M., Zhang, B., Mei, L., et al. (2025) · Glia · doi:10.1002/glia.70114 · Cited by 1 · see citing works
“Interestingly, these Lrp4+ cells were negative for GFAP (Figure 1E,F), a marker commonly associated with pial membrane-associated astrocytes (Falcone et al. 2020).”
Castro-Mendoza, P. B., Weaver, C. M., Chang, W., Medalla, M., Rockland, K. S., Lowery, L., McDonough, E. M., Varghese, M., Hof, P. R., Meyer, D. E., et al. (2024) · Brain Structure and Function · doi:10.1007/s00429-024-02819-y · Cited by 1 · see citing works
Self-citationDissecting Reactive Astrocyte Responses: Lineage Tracing and Morphology-based ClusteringPreprint
Delgado‐García, L. M., Ojalvo‐Sanz, A. C., Nakamura, T. K. E., Martín-López, E., Porcionatto, M. A., & López‐Mascaraque, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.01.587565 · Cited by 1 · see citing works
Astrocyte heterogeneity under physiological conditions and after brain injury
Mihailova, V., Morfov, S., Velikov, I., Spasov, R., Stoyanova, I. I., & Tonchev, A. B. (2023) · Varna Medical Forum · doi:10.14748/vmf.v12i1.8763
McNaughton, N., & Lages, Y. (2024) · Personality Neuroscience · doi:10.1017/pen.2024.1
Evolutionary Aspects of Glial Cells
Calì, C., Ackermans, N. L., Hof, P. R., & Magistretti, P. J. (2024) · Oxford University Press eBooks · doi:10.1093/med/9780197676592.003.0003
Self-citationUnexpected astrocyte gene flips image of brain’s ‘stalwart sentinels’
Schenkman, L. (2025) · The Transmitter · doi:10.53053/aeko5643
Glial cell interactions in neonatal hypoxic-ischemic injury
Ramljak, M., Andrade, M. F., Lacoste, B., Aguilar‐Valles, A., & Salmaso, N. (2025) · Glial health research. · doi:10.1016/j.ghres.2025.100006
Jeannelle, F., de la Maza, M. M., Schreiner, S., Hammer, G. P., Mirault, D., Mechawar, N., Brainbank Neuro-CEB Neuropathology Network, Bank, N. B., Mittelbronn, M. G. A., & Bouvier, D. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.19.671074
Astrocytes: Multiscale Molecular Targets for Glial Engineering and Interfaces
Konstantoulaki, A., Fabbri, R., Conte, G., Lazzarini, C., & Benfenati, V. (2025) · Springer eBooks · doi:10.1007/978-3-031-94215-0_1
Median Preoptic Astrocytes: Role in Sleep Regulation and Potential Mediators of Sex DifferencesPreprint
Onwukwe, C., Byrd, C., Viechweg, S. S., Black, D., & Mong, J. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.27.672605
“Supporting this hypothesis, E2 has been shown to suppress PGD2 release in the VLPO, a NREM promoting center in the brain, which may lead to increased arousal 158 .”
Morphological heterogeneity of human astrocytes in cerebral organoidsPreprint
Szederkenyi, K., Au, A., Attisano, L., Oheim, M., & Yip, C. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.18.675430
“Comparative analyses across 46 mammalian species, from rodents to primates, indicate that human ILAs exhibit the highest structural complexity (11).”
Conservation of glial density and cell-type ratios within a brain region across mammals
Pinto‐Duarte, A., Bogue, K., B, T. J. S. A., & Srinivasan, S. (2025) · PNAS Nexus · doi:10.1093/pnasnexus/pgaf314 · Cited by 2 · see citing works
“BG, basal ganglia; CX, cortex. white matter or reactive astrocytes (41), creating heterogeneous labeling that was helpful for observing interlaminar astrocytes found closer to the pia (42).”
Delgado‐García, L. M., Ojalvo‐Sanz, A. C., Nakamura, T. K. E., Martín-López, E., Porcionatto, M. A., & López‐Mascaraque, L. (2024) · Figshare · doi:10.6084/m9.figshare.26777254
Delgado‐García, L. M., Ojalvo‐Sanz, A. C., Nakamura, T. K. E., Martín-López, E., Porcionatto, M. A., & López‐Mascaraque, L. (2024) · Figshare · doi:10.6084/m9.figshare.26777257
The effect of astrocyte depletion and repopulation approaches in pathological condition of CNS
Tahmasebi, F., Safarian, A., Asl, E. R., Vahidinia, Z., & Barati, S. (2026) · Acta Neurologica Belgica · doi:10.1007/s13760-026-03005-z
Zhao, M., & Zhu, Y. (2026) · Computational and Structural Biotechnology Journal · doi:10.34133/csbj.0083
Blast injury leads to chronic shifts in protein expression of distinct astrocyte populations
Breehl, N., Priemer, D. S., Perl, D. P., & Juliano, S. L. (2026) · Brain Communications · doi:10.1093/braincomms/fcag263
Fisher, T. M., Limone, F., Smith, M. D., Wright, C., Kukanja, P., Lu, P., Limberg, K. C., Pirjanian, N., Zulueta, J., Fossati, V., et al. (2026) · Cell Reports · doi:10.64898/2026.07.29.741554 · Cited by 1 · see citing works
“Astrocytes are widely distributed throughout the CNS and are specifically well-positioned at sites of first contact with extravasating peripheral immune cells 46,47 .”
Ciuba, K. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06214-y
“These cells reside in the first cortical layer and project long, up to 2 mm, protrusions throughout the cortical layers [40, 41].”
- Authors
- Falcone, C., Penna, E., Hong, T., Tarantal, A. F., Hof, P. R., Hopkins, W. D., Sherwood, C. C., Noctor, S. C., & Martínez-Cerdeño, V.
- Affiliations
- Shriners Hospitals for Children - Northern California (US)
- University of California Davis Medical Center (US)
- University of California, Davis (US)
- Icahn School of Medicine at Mount Sinai (US)
- The University of Texas MD Anderson Cancer Center (US)
- George Washington University (US)
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
- ORCID
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-09-15
- Volume
- 31
- Issue
- 1
- Pages
- 379-395
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC7947181
- OpenAlex
- W3087591700
- Cited by
- 72
- References
- 46
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 20 · 2023: 14 · 2022: 9 · 2021: 3 · 2020: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Cerebral Cortex (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- SDL (submittedVersion)
- Funders
- National Science Foundation
- National Institute of Mental Health (#R01-MH113257)
- National Institutes of Health (NS092988)
- National Heart, Lung, and Blood Institute (R24-HL085794)
- California National Primate Research Center (P51-OD011107)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cortical astrocytes, astrocyte development, radial glia, prenatal development, postnatal development, glial fibrillary acidic protein, Pax6, SOX2, nestin, alphaB-crystallin, HOPX, S100β, aquaporin-4, GLAST, rhesus monkeys, chimpanzees, human, mice, primate brain evolution
- MeSH terms
- Animals, Astrocytes, Cerebral Cortex, Glial Fibrillary Acidic Protein, Humans, Macaca mulatta, Neurons, Biomarkers, Mice
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