Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination

Neuregulin 1 (NRG1) type III is a key mediator of Schwann cell development and myelination and is known to undergo proteolytic cleavage to produce an intracellular fragment. In this study, the authors show that this intracellular fragment of NRG1 modulates myelination by inducing the expression of a prostaglandin synthase (L-PGDS) which, in turn, leads to prostaglandin production and activation of GPR44. Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the prostaglandin D2 synthase ( L-pgds , also known as Ptgds ) gene, which, together with the G protein–coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.