Editors' ChoiceNeuroscience

Prostaglandin Promotes Myelination

Sci. Signal.  16 Dec 2014:
Vol. 7, Issue 356, pp. ec350
DOI: 10.1126/scisignal.aaa4770

Neuronal survival and function depends on a protective coating around axons called myelin. Axons in patients with peripheral neuropathy are often demyelinated. Neuregulin 1 (NRG1) type III is a transmembrane growth factor present in neurons that stimulates myelination by Schwann cells. NRG1 type III can itself be cleaved by a two-stage process involving γ-secretase, which generates an intracellular domain (ICD) that may be further processed to a smaller fragment. These intracellular fragments can modulate gene expression. Trimarco et al. found that primary rat dorsal root ganglia (DRG) neurons expressing NRG1 type III containing tags at the C- or N terminus exhibited loss of the C-tagged NRG1 from the cell membrane and accumulation in the nucleus when cocultured with Schwann cells; this was prevented by addition of a γ-secretase inhibitor. Among the array of induced genes in DRGs expressing NRG1 ICD, as well as in wild-type primary mouse DRGs cocultured with rat Schwann cells, expression of L-PGDS, which encodes prostaglandin D2 (PGD2) synthase, was most increased. Western blotting of NRG1 ICD-expressing DRGs and their conditioned medium showed that L-PGDS protein was primarily secreted from the cells, and that this increased the amount of PGD2 in the extracellular medium. Primary rat Schwann cells stimulated with PGD2 had increased phosphorylation of the transcription factor Nfatc4, which induces myelination by Schwann cells. Either adding an inhibitor of L-PGDS to the medium or knocking down GPR44 (a PGD2 receptor) in primary Schwann cells impaired the myelination of DRG neurons in organotypic myelinating cocultures. Sciatic nerves isolated from L-pgds-/- or Gpr44-/- mice were less myelinated than those from wild-type mice. The findings suggest that NRG1 stimulates axon-to-Schwann cell communication through PGD2 synthesis, which in turn promotes Schwann cells to myelinate axons. The identification of this intercellular feedback loop may aid in the development of therapies for peripheral neuropathies.

A. Trimarco, M. Grazia Forese, V. Alfieri, A. Lucente, P. Brambilla, G. Dina, D. Pieragostino, P. Sacchetta, Y. Urade, B. Boizet-Bonhoure, F. Martinelli Boneschi, A. Quattrini, and C. Taveggia, Prostaglandin D2 synthase/GPR44: A signaling axis in PNS myelination. Nat. Neurosci. 17, 1682–1692 (2014). [PubMed]