Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate

Weam S Shahin; Shima O Ebed; Scott R Tyler; Branko Miljkovic; Soon H Choi; Yulong Zhang; Weihong Zhou; Idil A Evans; Charles Yeaman; John F Engelhardt

doi:10.1038/s41467-023-36174-z

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Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate

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Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate

Weam S Shahin, Shima O Ebed, Scott R Tyler, Branko Miljkovic, Soon H Choi, Yulong Zhang, Weihong Zhou, Idil A Evans, Charles Yeaman and John F Engelhardt

Nature communications, Vol.14(1), 444

01/27/2023

DOI: 10.1038/s41467-023-36174-z

PMCID: PMC9883463

PMID: 36707536

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Abstract

Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrains NSCs to a self-renewing state and prevents neurosphere formation. Ncf1-dependent oxidation of Igfbp2 promotes neurogenesis by NSCs in vitro and in vivo while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1 and Igfbp2 NSCs favor the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induces DDSBs and is sufficient to rescue the ability of Ncf1 and Igfbp2 NSCs to lineage-commit to form neurospheres and neurons. NSC lineage commitment is dependent on the oxidizable cysteine-43 residue of Igfbp2. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.

Details

Title: Subtitle: Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate
Creators: Weam S Shahin - University of Iowa
Shima O Ebed - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Scott R Tyler - University of Iowa
Branko Miljkovic - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Soon H Choi - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Yulong Zhang - University of Iowa
Weihong Zhou - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Idil A Evans - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Charles Yeaman - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
John F Engelhardt - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. john-engelhardt@uiowa.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.14(1), 444
DOI: 10.1038/s41467-023-36174-z
PMID: 36707536
PMCID: PMC9883463
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Language: English
Date published: 01/27/2023
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984362692702771

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