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Nrf2 inhibition affects cell cycle progression during early mouse embryo development.

Ying Lin1,2, Liu-Cai Sui1, Rong-Hua Wu1

  • 1Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China.

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Brusatol halts early mouse embryo development by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2). This Nrf2 inhibition causes cell cycle arrest, preventing crucial cell division for embryonic growth.

Keywords:
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Area of Science:

  • Reproductive Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor crucial for cellular defense mechanisms.
  • While Nrf2's role in tumor development is extensively studied, its function in early embryogenesis remains less understood.
  • Brusatol, a quassinoid from Brucea javanica, is known to inhibit Nrf2 activity.

Purpose of the Study:

  • To investigate the critical roles of Nrf2 in mouse early embryonic development.
  • To determine the effects of brusatol, an Nrf2 inhibitor, on zygotic development.
  • To elucidate the molecular mechanisms underlying brusatol-induced developmental arrest.

Main Methods:

  • Treatment of mouse zygotes with brusatol.
  • Assessment of early embryo development and cell cycle progression.
  • Quantitative analysis of cell cycle-related gene expression (CDK1, cyclin B).
  • Rescue experiments using Nrf2 CRISPR activation plasmid injection.

Main Results:

  • Brusatol treatment significantly inhibited early mouse embryo development, with most embryos arresting at the two-cell stage.
  • This developmental arrest was correlated with cell cycle arrest.
  • mRNA levels of CDK1 and cyclin B were reduced in brusatol-treated embryos.
  • Partial rescue of embryo development was observed upon Nrf2 activation via CRISPR plasmid injection.

Conclusions:

  • Brusatol inhibits early mouse embryonic development by targeting Nrf2.
  • The mechanism involves Nrf2-dependent cell cycle arrest at the G2 to M phase transition, mediated by the cyclin B-CDK1 complex.
  • Nrf2 plays a critical role in regulating cell cycle progression essential for early embryonic development.