Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling
Kimberly K. Hoi,
Wenlong Xia,
Ming Ming Wei,
Maria Jose Ulloa Navas,
Jose-Manuel Garcia Verdugo,
Maxence V. Nachury,
Jeremy F. Reiter,
Stephen P.J. Fancy
Affiliations
Kimberly K. Hoi
Departments of Neurology and Pediatrics, Division of Neuroimmunology and Glial Biology, Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Wenlong Xia
Departments of Neurology and Pediatrics, Division of Neuroimmunology and Glial Biology, Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Ming Ming Wei
Departments of Neurology and Pediatrics, Division of Neuroimmunology and Glial Biology, Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Maria Jose Ulloa Navas
Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, 46980 Paterna, Spain
Jose-Manuel Garcia Verdugo
Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, 46980 Paterna, Spain
Maxence V. Nachury
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA
Jeremy F. Reiter
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
Stephen P.J. Fancy
Departments of Neurology and Pediatrics, Division of Neuroimmunology and Glial Biology, Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of 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 Hedgehog (Hh) and G-protein-coupled receptor (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 because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because 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.
