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Mitogen-activated protein kinase p38 regulates Krox-20 to direct Schwann cell differentiation and peripheral

Shireen Hossain1, Miguel-Angel de la Cruz-Morcillo, Ricardo Sanchez-Prieto

  • 1Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.

Glia
|April 19, 2012
PubMed

Insights

Extracellular matrix (ECM) activates p38, a key signaling pathway that drives Schwann cell differentiation and peripheral myelination by regulating Krox-20 expression through downstream effectors like MK2 and MSK-1/CREB.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Extracellular matrix (ECM) extracts activate mitogen-activated protein kinase (MAPK) p38 in co-cultures of rat Schwann cells and dorsal root ganglion neurons (DRGNs).
  • p38 activation is crucial for initiating myelination, while its inhibition blocks this process.

Purpose of the Study:

  • To investigate the downstream signaling molecules regulated by p38 that are essential for Schwann cell differentiation and myelination.
  • To determine the role of p38 in regulating key transcription factors and kinases involved in peripheral nerve development.

Main Methods:

  • Utilized p38 pharmacological inhibitors and gene silencing (siRNAs) in Schwann cell-DRGN co-cultures.
  • Assessed the expression of the transcription factor Krox-20, cell cycle inhibitor p27(kip1), and myelin proteins (MBP, MAG) using immunocytochemistry and qRT-PCR.
  • Investigated the roles of downstream kinases MAPK-activated protein kinase-2 (MK2) and mitogen and stress-activated protein kinase-1 (MSK-1), and transcription factor cAMP response element-binding protein (CREB).

Main Results:

  • p38α directly regulates Krox-20 expression, a critical factor for initiating myelination.
  • p38 activity is necessary for the expression of p27(kip1), linked to Schwann cell differentiation.
  • Inhibition of MK2 or CREB, and MSK-1/CREB signaling, reduced Krox-20 and myelin protein expression.
  • p38 modulated SCIP and Sox10 expression, transcription factors involved in Krox-20 regulation.

Conclusions:

  • p38 signaling is a primary driver of Schwann cell differentiation and peripheral myelination.
  • The p38 pathway regulates Krox-20 expression via downstream effectors MK2 and MSK-1/CREB, and transcription factors SCIP and Sox10.
  • This pathway is essential for the timely onset of myelination in the peripheral nervous system.

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