Extracellular HSPA5/Grp78/BiP, Acting through Its Receptor Plexin-B3 and Nkx2.8, Regulates Oligodendrocyte Myelination in Mice

Abstract

Myelin sheaths are generated from differentiated plasma membranes of oligodendroglial cells (oligodendrocytes) during development. Despite detailed functional studies, such as aiding nerve conduction velocity, it remains unclear which extracellular signals from neurons interact with oligodendrocytes to control oligodendrocyte development and how these are achieved. Herein, we demonstrate that the Plexin molecule Plexin-B3, generally known as a receptor for Sema family signaling proteins, is specifically expressed in oligodendrocytes and plays a key role in promoting oligodendrocyte maturation and myelination. Oligodendrocyte-specific conditional male knock-out mice of Plexin-B3 exhibited decreased myelin thickness and myelin marker protein expression, compared with littermate controls. Unexpectedly, we identified heat shock protein family A member 5 (HSPA5)/Grp78/BiP as the neuron-secreted ligand of Plexin-B3. Indeed, neuron-specific knockdown of HSPA5 in male mice revealed a critical role for myelin thickness not only at the biochemical level but also at the histochemical one. Furthermore, the transcription factor Nkx2.8, which plays a role in oligodendrocytes, was identified as a potential mediator of Plexin-B3 signaling. Our results suggest that the interaction of extracellular HSPA5 with Plexin-B3 on oligodendrocytes, acting possibly through Nkx2.8, regulates oligodendrocyte maturation and myelination. This ligand and receptor interaction and a downstream molecule are newly added to the list of emerging signaling units controlling myelination.