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Ferrodifferentiation regulates neurodevelopment via ROS generation.

Shiyang Chang1,2,3, Peina Wang1,2, Yingying Han1

  • 1Laboratory of Molecular Iron Metabolism, Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry, and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.

Science China. Life Sciences
|March 17, 2023
PubMed
Summary

Iron is crucial for neural differentiation. Severe iron deficiency in stem cells and fetal mice significantly inhibits neurogenesis, a process termed ferrodifferentiation.

Keywords:
ESCsIRPsROSdifferentiationironneurodevelopment

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Iron is essential for numerous biological processes, including development.
  • The precise role of intracellular iron levels in regulating neural differentiation remains largely unknown.
  • Iron-regulatory proteins (IRPs) are key mediators of cellular iron homeostasis.

Purpose of the Study:

  • To investigate the impact of iron deficiency on neural differentiation using knockout models.
  • To elucidate the underlying molecular mechanisms by which iron levels influence neurogenesis.
  • To introduce and define the concept of 'ferrodifferentiation'.

Main Methods:

  • Utilized iron-regulatory proteins (IRP1 and IRP2) knockout embryonic stem cells (ESCs) to create iron-deficient models.
  • Induced neural differentiation in ESCs and analyzed neuronal precursor markers (Pax6, Sox2) and neuronal fibers (Tuj1).
  • Conducted in vivo studies involving knockdown of IRP1 in IRP2 knockout fetal mice to assess effects on neurogenesis and neuronal migration.

Main Results:

  • IRP1-/-IRP2-/- ESCs exhibited significantly reduced neuronal precursor cells and Tuj1 fibers upon neural induction.
  • Knockdown of IRP1 in IRP2-/- fetal mice impaired neuronal precursor differentiation and neuronal migration.
  • Iron supplementation to IRP1-/-IRP2-/- ESCs restored normal neural differentiation.
  • Low iron levels led to increased reactive oxygen species (ROS) production and down-regulation of iron-sulfur cluster protein ISCU, impacting stem cell proliferation and differentiation.

Conclusions:

  • Low intracellular iron status significantly inhibits neural differentiation, a process termed ferrodifferentiation.
  • Appropriate iron levels are critical for maintaining normal neurogenesis and neuronal development.
  • The mechanism involves ROS production and altered ISCU expression due to iron deficiency.