Entrainment of the Circadian Clock in Neural Stem Cells by Epidermal Growth Factor is Closely Associated with ERK1/2-mediated Induction of Multiple Clock-related Genes

Asuka Mogi, Ryo Yomoda, Syunya Kimura, Chisato Tsushima, Jun Takouda, Miho Sawauchi, Tomoko Maekawa, Hidenobu Ohta, Satoshi Nishino, Masatake Kurita, Nariyasu Mano, Noriko Osumi, Takahiro Moriya

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The mitotic activity of certain tissues in the body is closely associated with circadian clock function. However, the effects of growth factors on the molecular clockwork are not fully understood. Stimulation of neural stem cells (NSCs) with epidermal growth factor (EGF), a well-known mitogen, is known to cause synchronized cell cycle progression with a period of approximately 24 h, closely associated with the Per2 gene expression rhythm. Here, we examined the effects of EGF on the molecular clockwork of NSCs. Treatment of cultured NSCs derived from embryonic mouse forebrain with EGF (20 ng/mL) caused a phase shift in the PER2::LUCIFERASE bioluminescence rhythm in a stimulation time-dependent manner. The EGF phase-response curve differed from that of forskolin (FK)—a well-known chemical resetting stimulus—both in the advance/delay ratio and stimulation time-dependency. PCR array analysis followed by quantitative PCR validation demonstrated that EGF treatment transiently induced multiple clock-related genes including Per1, Per2, Dec1, e4bp4, and Noct, whereas FK treatment induced a limited number of genes (Per1 and Dec1), suggesting that the mode of entrainment of NSC molecular clock was different for EGF and FK. EGF led to gene induction in the presence of cycloheximide, suggesting that de novo protein synthesis is unnecessary. Pretreatment with the MEK1/2 inhibitor U0126 significantly suppressed the acute induction of Per2, Dec1, and Noct by EGF and also abolished the EGF-induced phase shift of the PER2::LUCIFERASE rhythm in NSCs. These results suggest a unique effect of EGF on the molecular clockwork of NSCs.

Original languageEnglish
Pages (from-to)45-66
Number of pages22
JournalNeuroscience
Volume379
DOIs
Publication statusPublished - 2018 May 21

Keywords

  • circadian rhythm
  • clock gene
  • epidermal growth factor
  • neural stem cell

ASJC Scopus subject areas

  • Neuroscience(all)

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