Shh Signaling through the Primary Cilium Modulates Rat Oligodendrocyte Differentiation

• Published in: PloS one Vol. 10; no. 7; p. e0133567
• Main Authors: Falcón-Urrutia, Paulina, Carrasco, Carlos M, Lois, Pablo, Palma, Veronica, Roth, Alejandro D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28-07-2015; Public Library of Science (PLoS)
• Subjects: Animals; Biology; Cell culture; Cell cycle; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell growth; Cells, Cultured; Cilia; Cilia - metabolism; Cilia - ultrastructure; Differentiation; Genomes; Glial stem cells; Growth factors; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hedgehog Proteins - pharmacology; Kinases; Localization; Nervous system; Oligodendrocytes; Oligodendroglia - cytology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Pathways; Platelet-derived growth factor; Platelet-Derived Growth Factor - metabolism; Platelet-Derived Growth Factor - pharmacology; Quinazolinones - pharmacology; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Rodents; Science; Signal Transduction; Signaling; Stem cells; Survival; Veratrum Alkaloids - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0133567

Primary Cilia (PC) are a very likely place for signal integration where multiple signaling pathways converge. Two major signaling pathways clearly shown to signal through the PC, Sonic Hedgehog (Shh) and PDGF-Rα, are particularly important for the proliferation and differentiation of oligodendrocytes, suggesting that their interaction occurs in or around this organelle. We identified PC in rat oligodendrocyte precursor cells (OPCs) and found that, while easily detectable in early OPCs, PC are lost as these cells progress to terminal differentiation. We confirmed the interaction between these pathways, as cyclopamine inhibition of Hedgehog function impairs both PDGF-mediated OPC proliferation and Shh-dependent cell branching. However, we failed to detect PDGF-Rα localization into the PC. Remarkably, ciliobrevin-mediated disruption of PC and reduction of OPC process extension was counteracted by recombinant Shh treatment, while PDGF had no effect. Therefore, while PDGF-Rα-dependent OPC proliferation and survival most probably does not initiate at the PC, still the integrity of this organelle and cilium-centered pathway is necessary for OPC survival and differentiation.