UCSF

After damage to white matter tracts in central nervous system (CNS) diseases such as multiple sclerosis (MS), myelin sheaths can be regenerated by activated oligodendrocyte precursor cells (OPCs). Failure of this remyelination program often occurs due to the improper expansion of the OPC population within sites of injury, contributing significantly to ongoing neurological dysfunction and disease progression. Understanding the biological underpinnings of developmental myelination and remyelination will reveal novel therapeutic strategies for disorders involving dysfunctional myelin regeneration. Importantly, OPCs dynamically produce primary cilia, microtubule-based organelles that transduce cues in a specialized signaling compartment. Here, we show that OPCs require primary cilia to respond properly to white matter injury (WMI). We demonstrate that removing primary cilia from OPCs results in significantly reduced OPC proliferation during both CNS development and WMI repair. Furthermore, we uncover a role for cAMP and CREB-mediated transcription, but not Hedgehog (Hh) signaling, in the ciliary control of OPC proliferation. This leads us to propose a G-protein coupled receptor (GPCR)/cAMP/CREB signaling axis initiated at the primary cilium as a crucial regulator of OPC biology. These findings advance our understanding of how OPCs coordinate complex cellular cues during remyelination in the CNS and presents the primary cilium as an organelle from which novel targets for remyelinating therapies may be identified.