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

Weam S Shahin1, Shima O Ebed1, Scott R Tyler1

  • 1Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.

Nature Communications
|January 27, 2023
PubMed

Insights

Reactive oxygen species (ROS) regulate neural stem cells (NSCs) via Igfbp2 signaling, impacting DNA repair and cell fate. This study reveals how ROS-dependent Igfbp2 oxidation balances NSC self-renewal and differentiation.

Area of Science:

  • Neuroscience
  • Stem Cell Biology
  • Genetics

Background:

  • Neural stem cell (NSC) behavior is influenced by reactive oxygen species (ROS), but the underlying mechanisms are not fully understood.
  • ROS are known to play a role in regulating cell functions, including stem cell maintenance and differentiation.

Purpose of the Study:

  • To elucidate the mechanisms by which ROS control NSC self-renewal and lineage commitment.
  • To investigate the role of Igfbp2 signaling in ROS-mediated regulation of DNA repair pathways in NSCs.

Main Methods:

  • Utilized Ncf1 and Igfbp2 knockout mouse models to study NSC behavior in vitro and in vivo.
  • Analyzed DNA damage response genes, including Brca1, and DNA double-strand breaks (DDSBs) in NSCs.
  • Investigated the role of the oxidizable cysteine-43 residue of Igfbp2 in NSC lineage commitment.

Main Results:

  • Ncf1 or Igfbp2 deficiency resulted in NSCs remaining in a self-renewing state, inhibiting neurosphere formation.
  • Ncf1-dependent Igfbp2 oxidation promoted neurogenesis by NSCs, repressed Brca1, and induced DDSBs.
  • Ncf1-/- and Igfbp2-/- NSCs preferentially differentiated into oligodendrocytes.
  • Transient repression of Brca1 rescued the lineage commitment defect in Ncf1-/- and Igfbp2-/- NSCs.
  • NSC lineage commitment was dependent on the oxidizable cysteine-43 residue of Igfbp2.

Conclusions:

  • ROS-dependent Igfbp2 signaling acts as a critical regulator of DNA repair pathways, balancing NSC self-renewal and lineage commitment.
  • DNA damage and repair mechanisms, orchestrated by redox-regulated Igfbp2, are crucial for determining NSC fate decisions.

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