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Myelin-associated glycoprotein inhibits microtubule assembly by a Rho-kinase-dependent mechanism

Fumiaki Mimura1, Satoru Yamagishi, Nariko Arimura

  • 1Department of Neurobiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670.

The Journal of Biological Chemistry
|April 6, 2006
PubMed

Insights

Myelin inhibitors like MAG block nerve regeneration by affecting CRMP-2 protein phosphorylation and microtubule stability. CRMP-2

Area of Science:

  • Neuroscience
  • Cell Biology
  • Regenerative Medicine

Background:

  • Myelin-associated glycoprotein (MAG) and Nogo inhibit central nervous system (CNS) axonal regeneration.
  • RhoA and Rho-kinase signaling are implicated in these inhibitory mechanisms.

Purpose of the Study:

  • To investigate the role of collapsing response mediator protein-2 (CRMP-2) in MAG- and Nogo-mediated inhibition of neurite outgrowth.
  • To elucidate the involvement of CRMP-2 phosphorylation and microtubule dynamics in the inhibitory signaling pathways.

Main Methods:

  • Investigated CRMP-2 phosphorylation by Rho-kinase downstream of MAG/Nogo-66.
  • Utilized overexpression of nonphosphorylated CRMP-2 and dominant-negative CRMP-2.
  • Employed small interference RNA (siRNA) for CRMP-2 gene knockdown.
  • Assessed microtubule levels in response to MAG stimulation and after spinal cord injury.

Main Results:

  • CRMP-2 is phosphorylated by Rho-kinase in response to MAG/Nogo-66.
  • Nonphosphorylated CRMP-2 counteracts MAG's inhibitory effects on cerebellar neurons.
  • CRMP-2 knockdown mimics MAG's inhibitory effects.
  • MAG stimulation down-regulates microtubule density, an effect also seen in injured axons and dependent on Rho-kinase.

Conclusions:

  • CRMP-2 plays a crucial role in mediating the inhibitory effects of myelin-derived proteins on axon regeneration.
  • Microtubule destabilization, regulated by CRMP-2 and Rho-kinase, is a key mechanism underlying the failure of CNS axon regeneration.

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