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FoxO3 Modulates Circadian Rhythms in Neural Stem Cells.

Swip Draijer1, Raissa Timmerman1, Jesse Pannekeet1

  • 1Swammerdam Institute of Life Sciences, University of Amsterdam, 1018 WB Amsterdam, The Netherlands.

International Journal of Molecular Sciences
|September 9, 2023
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The transcription factor FoxO3 disrupts circadian rhythms in neural stem cells by regulating Clock gene expression. Loss of FoxO3 also delays the timing of neural stem cell proliferation in the hippocampus.

Keywords:
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Area of Science:

  • Neuroscience
  • Cell Biology
  • Chronobiology

Background:

  • FoxO transcription factors and the circadian clock regulate metabolism, cell cycle, and stem cell homeostasis.
  • FoxO3 is known to preserve adult neural stem cells and regulate liver circadian rhythms.
  • The role of FoxO3 in neural stem cell circadian rhythms was previously unknown.

Purpose of the Study:

  • To investigate whether FoxO3 regulates circadian rhythms in neural stem cells.
  • To determine the mechanism by which FoxO3 influences neural stem cell circadian rhythmicity.
  • To examine the impact of FoxO3 deficiency on neural stem cell proliferation timing in vivo.

Main Methods:

  • Disruption of circadian rhythmicity in neural stem cell cultures lacking FoxO3.
  • Assessment of circadian rhythmicity at the single-cell level using a Rev-Erbα-VNP reporter.
  • Meta-analysis of published data on circadian clock component co-occupancy with FoxO3.
  • Analysis of hippocampal neural stem cell proliferation in FoxO3-deficient mice.

Main Results:

  • Loss of FoxO3 disrupts circadian rhythmicity in neural stem cell cultures by regulating Clock transcriptional levels.
  • Circadian rhythmicity is maintained at the single-cell level in the absence of FoxO3.
  • Meta-analysis confirms FoxO3 is a Clock-controlled gene with co-occupancy by multiple circadian components.
  • FoxO3 deficiency delays the circadian phase of hippocampal neural stem cell proliferation in mice.

Conclusions:

  • FoxO3 plays a critical role in regulating circadian rhythms within neural stem cells.
  • FoxO3 influences the timing of neural stem cell proliferation, impacting overall homeostasis.
  • These findings establish FoxO3 as a key component of the circadian regulation of neural stem cell biology.