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The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation

Yoon Kyung Shin1, So Young Jang, Joo Youn Park

  • 1Department of Physiology and Mitochondria Hub Regulation Center (MHRC), College of Medicine, Dong-A University, Busan, South Korea.

Glia
|March 19, 2013
PubMed

Insights

Active Rac1 GTPase (Rac) negatively regulates Schwann cell differentiation after nerve injury by upregulating c-jun via the MKK7-JNK pathway, promoting axon regeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Schwann cells dedifferentiate and produce neurotrophic factors post-nerve injury, aiding axon regeneration.
  • The Raf-ERK pathway and c-jun expression were previously implicated in these Schwann cell responses.

Purpose of the Study:

  • To investigate the role of Rac1 GTPase (Rac) in regulating Schwann cell differentiation and gene expression following nerve injury.
  • To elucidate the specific signaling pathways involved in Rac-mediated Schwann cell responses.

Main Methods:

  • Primary Schwann cell cultures and sciatic nerve explant cultures were utilized.
  • Rac inhibition, MKK7-JNK and Raf-ERK pathway analyses, and microarray experiments were performed.
  • ErbB2 signaling inhibition was employed to study its effect on the pathway.

Main Results:

  • Active Rac1 inhibits Schwann cell differentiation by upregulating c-jun and downregulating Krox20 via the MKK7-JNK pathway.
  • Rac inhibition blocked MKK7 activation and c-jun induction in sciatic nerves post-axotomy.
  • Regeneration-associated gene expression was dependent on Rac, but not ERK.
  • ErbB2 signaling inhibition prevented MKK7 activation, c-jun induction, and Rac-dependent gene expression.

Conclusions:

  • The neuregulin-Rac-MKK7-JNK/c-jun pathway is a key regulator of Schwann cell dedifferentiation after nerve injury.
  • Rac acts as a crucial negative regulator of Schwann cell differentiation, promoting regenerative responses.

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