Primary cilia control Oligodendrocyte Precursor Cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis due to improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hh and GPCR signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions due to reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals, but instead leads to dysfunctional cAMP-dependent CREB-mediated transcription. As inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI. Overall design: To investigate the function of cilia in oligodendrocyte precursor cells, RNA-sequencing was performed on OPCs isolated from the cortices of 4-6 mice for each sample at P11. OPCs were isolated from mice in which cilia were conditionally deleted using Ift88 floxed allele (Ift88 cKO). Mice containing one wildtype copy of Ift88 were used as controls. A total of 3 Ift88 cKO and 3 control samples were used for this study.