OSCR

Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair.

Overview

Authors: Wenlong Xia1, Laura Morcom2,3, Zhaoyang Xu2,3,4,5, I-Ling Lu6, Qing Wang7, Kimberly K Hoi1, Mingming Wei1, Keying Zhu1, Gregory Jordan2,3, Xiao-Yan Tang1, Julio Gonzalez-Maya1, Vanesa S Mattera1, Sophia M Panigrahi1, Riki Kawaguchi7, Ben Emery8, Santos J Franco9, Daniel H Geschwind7, Brian Popko10, David H Rowitch2,3,4,5,6, Stephen P J Fancy1
ORCID iDs: Laura Morcom, I-Ling Lu, Keying Zhu, Riki Kawaguchi, Ben Emery, Brian Popko, David H Rowitch, Stephen P J Fancy
  1. Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco, San Francisco, CA USA
  2. Department of Paediatrics, University of Cambridge, Cambridge, UK
  3. Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
  4. Department of Pediatrics, Cedars Sinai Guerin Children’s, Los Angeles, CA USA
  5. Department of Neurosurgery, Cedars Sinai Guerin Children’s, Los Angeles, CA USA
  6. Institute for Regenerative Medicine, University of California, San Francisco, San Francisco, CA USA
  7. Department of Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
  8. Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR USA
  9. Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO USA
  10. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL USA
Institutions: University of California, San Francisco (United States); Wellcome/MRC Cambridge Stem Cell Institute (United Kingdom); University of Cambridge (United Kingdom); Cedars-Sinai Medical Center (United States); University of California, Los Angeles (United States); Oregon Health & Science University (United States); University of Colorado Anschutz (United States); Northwestern University (United States)
Journal: Nature, volume 653, issue 8115, pages 819-830
Dates: received 30 April 2025; accepted 17 February 2026; published online 1 April 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41586-026-10290-4 · PMID 41922774 · PMCID PMC13190340 · OpenAlex W7146946498
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), other condition (population)
Methods: Statistics, Evoked potentials
Keywords: Neural progenitors, Neuronal development
MeSH: Cerebral Cortex*, DNA Repair*, Homeodomain Proteins*, Neurons*, Nuclear Proteins*, Repressor Proteins*, Activating Transcription Factor 4, Animals, Ataxia Telangiectasia Mutated Proteins, DNA Damage, Female, Male, Mice, Phosphorylation, RNA-Binding Proteins, Tumor Suppressor Protein p53 (* major topic)
Topic: DNA Repair Mechanisms (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: European Research Council (789054); NINDS NIH HHS (P01 NS083513, R01 NS120981); National Institute for Health Research (NIHR) (NIHR203312)
Citations: cited by 2 papers (Europe PMC); 56 references in the paper

Abstract

During mammalian evolution, excitatory neurons in upper cortical layer 2 and layer 3 (L2/3) have shown a disproportionate expansion compared with other layers1–4. Replicative expansion of cortical neural progenitors is associated with considerable oxidative DNA damage. Here we show that activating transcription factor 4 (ATF4) has roles as a critical regulator of the DNA damage response, directly activating components of double-stranded DNA repair, including CIRBP, UBA52 and EBF1. Notably, pan-cortical knockout (Emx1-Cre;Atf4fl/fl) demonstrates that ATF4 is required specifically for the development of upper layer 2/3 neurons, marked by the expression of cut-like homeobox 2 protein, CUX2. ATF4 functions to repair DNA damage and attenuate cell death of embryonic radial glial progenitors in a p53-dependent manner. In particular, we show that cold inducible RNA-binding protein (CIRBP) is a transcriptional target of ATF4 that is required for normal phosphorylation of the key double-strand DNA repair factor ataxia telangiectasia mutated (ATM). These findings establish that ATF4 is an essential regulator of the DNA damage response. They further indicate that there are extraordinary requirements for DNA repair after replicative stress in CUX2+ neurons during mammalian brain development.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The single-nucleus RNA sequencing data from E11.5 mouse brains generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE314470 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314470). All other data supporting the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Publisher: n/a → Nature Portfolio

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 2 keywords, 16 MeSH terms, 3 funders, 56 references.

Cite

This paper

Xia, W., Morcom, L., Xu, Z., Lu, I.-L., Wang, Q., Hoi, K. K., Wei, M., Zhu, K., Jordan, G., Tang, X.-Y., Gonzalez-Maya, J., Mattera, V. S., Panigrahi, S. M., Kawaguchi, R., Emery, B., Franco, S. J., Geschwind, D. H., Popko, B., Rowitch, D. H., & Fancy, S. P. J. (2026). Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair. Nature, 653(8115), 819-830. https://doi.org/10.1038/s41586-026-10290-4

BibTeX

@article{xia2026expansion,
author = {Xia, Wenlong and Morcom, Laura and Xu, Zhaoyang and Lu, I-Ling and Wang, Qing and Hoi, Kimberly K and Wei, Mingming and Zhu, Keying and Jordan, Gregory and Tang, Xiao-Yan and Gonzalez-Maya, Julio and Mattera, Vanesa S and Panigrahi, Sophia M and Kawaguchi, Riki and Emery, Ben and Franco, Santos J and Geschwind, Daniel H and Popko, Brian and Rowitch, David H and Fancy, Stephen P J},
title = {{Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair}},
journal = {Nature},
year = {2026},
month = apr,
volume = {653},
number = {8115},
pages = {819--830},
publisher = {Nature Portfolio},
issn = {0028-0836},
doi = {10.1038/s41586-026-10290-4},
url = {https://doi.org/10.1038/s41586-026-10290-4},
pmid = {41922774},
pmcid = {PMC13190340}
}

RIS

TY - JOUR
AU - Xia, Wenlong
AU - Morcom, Laura
AU - Xu, Zhaoyang
AU - Lu, I-Ling
AU - Wang, Qing
AU - Hoi, Kimberly K
AU - Wei, Mingming
AU - Zhu, Keying
AU - Jordan, Gregory
AU - Tang, Xiao-Yan
AU - Gonzalez-Maya, Julio
AU - Mattera, Vanesa S
AU - Panigrahi, Sophia M
AU - Kawaguchi, Riki
AU - Emery, Ben
AU - Franco, Santos J
AU - Geschwind, Daniel H
AU - Popko, Brian
AU - Rowitch, David H
AU - Fancy, Stephen P J
TI - Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair
T2 - Nature
J2 - Nature
PY - 2026
DA - 2026/04/01
VL - 653
IS - 8115
SP - 819
EP - 830
SN - 0028-0836
PB - Nature Portfolio
DO - 10.1038/s41586-026-10290-4
UR - https://doi.org/10.1038/s41586-026-10290-4
LA - en
ER -

CSL-JSON

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