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The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling

Liang Yuh Chew1, Heng Zhang2, Jianzheng He2

  • 1Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.

Cell Reports
|August 4, 2021
PubMed

Insights

The Nrf2-Keap1 pathway governs neuronal remodeling during fly metamorphosis, activated by steroid hormones. This pathway regulates dendrite pruning via proteasomal degradation, independent of its antioxidant role.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • The Nrf2-Keap1 pathway is crucial for cellular protection against oxidative stress.
  • Dysfunctional Nrf2 is linked to human diseases like cancer and neurodegeneration.
  • Its role in nervous system development remains largely unknown.

Purpose of the Study:

  • To investigate the function of the Nrf2-Keap1 pathway in neuronal development.
  • To elucidate the regulatory mechanisms of this pathway during nervous system remodeling.
  • To determine the specific role of Nrf2-Keap1 signaling in neuronal remodeling.

Main Methods:

  • Utilized Drosophila melanogaster as a model organism.
  • Investigated the Nrf2-Keap1 pathway components (CncC/Nrf2, Keap1, MafS).
  • Examined the interplay between Nrf2-Keap1 signaling, ecdysone, and neuronal remodeling processes like dendrite pruning.

Main Results:

  • Demonstrated a cell-autonomous role for the Nrf2-Keap1 pathway in governing neuronal remodeling during Drosophila metamorphosis.
  • Showed Nrf2-Keap1 signaling is activated downstream of the steroid hormone ecdysone.
  • Revealed that Nrf2-Keap1 signaling regulates dendrite pruning through proteasomal degradation, independent of its canonical antioxidant functions.

Conclusions:

  • Established an epistatic link between the Nrf2-Keap1 pathway and steroid hormone signaling in neuronal development.
  • Highlighted an antioxidant-independent, proteasome-dependent function of the Nrf2-Keap1 pathway in neuronal remodeling.
  • Provided new insights into the complex regulation of nervous system development and repair.
Keywords:
CncCDrosophilaNrf2-Keap1 pathwayantioxidantcytoplasm-to-nucleus translocationdendrite pruningecdysone signalingmetamorphosisremodelingsteroid hormone

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