Editors' ChoiceNeuroscience

Initiating Myelination

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Science Signaling  15 Sep 2009:
Vol. 2, Issue 88, pp. ec307
DOI: 10.1126/scisignal.288ec307

Contact between axons of the peripheral nervous system (PNS) and Schwann cells is required for Schwann cells to produce the myelin sheaths that electrically insulate these axons. An as-yet-unidentified signal from the axon increases cyclic adenosine monophosphate (cAMP) within the Schwann cell, leading to activation of protein kinase A (PKA) and the subsequent expression of oct6 and krox20, which encode transcription factors required for the production of myelin basic protein (MBP), a component of the myelin sheath. Monk et al. (see the Perspective by Meijer) report that the orphan G protein–coupled receptor (GPCR) gpr126 is required in Schwann cells for the increase in cAMP induced by axonal contact. In zebrafish that carried loss-of-function mutations in gpr126, there was no myelination of sensory or motor neurons, and Schwann cells stopped developing at the promyelination stage and failed to express oct6 and krox20. Because signaling by neuregulin 1 (Nrg1) through the ErbB2 and ErbB3 receptors can also activate oct6 expression and the myelination program, the authors examined expression of nrg1 and erbb3 in gpr126 mutants, where they found no abnormalities. Similarly, gpr126 expression was not affected in erbb2 mutants, which suggests that Nrg1 signaling and signaling through gpr126 may regulate myelination independently. Treating mutant embryos with forskolin, which increases cAMP production, rescued the myelination phenotype and restored oct6 and krox20 expression in gpr126 mutants but did not rescue myelination or mbp expression in krox20 mutants, indicating that the increase in cAMP in Schwann cells occurs upstream of the activation of krox20 by Oct6. Because many GPCRs signal through cAMP, the authors propose that signaling through gpr126 in Schwann cells stimulates cAMP production to activate the myelination program.

K. R. Monk, S. G. Naylor, T. D. Glenn, S. Mercurio, J. R. Perlin, C. Dominguez, C. B. Moens, W. S. Talbot, A G protein–coupled receptor is essential for Schwann cells to initiate myelination. Science 325, 1402–1405 (2009). [Abstract] [Full Text]

D. Meijer, Went fishing, caught a snake. Science 325, 1353–1354 (2009). [Summary] [Full Text]

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