The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

Abstract

Reversible cell cycle arrest (quiescence/G0) is characteristic of adult stem cells and is actively controlled at multiple levels. G0 cells extend a primary cilium, which functions as a signaling hub, but how it controls the quiescence program is not clear. Here, we report that primary cilia distinguish different states of cell cycle exit: quiescent myoblasts elaborate a primary cilium in vivo and in vitro, but terminally differentiated myofibers do not. Myoblasts where ciliogenesis is ablated using RNAi against a key ciliary assembly protein (IFT88) can exit the cell cycle but display an altered quiescence program and impaired self-renewal. Specifically, the G0 transcriptome in IFT88 knockdown cells is aberrantly enriched for G2/M regulators, suggesting a focused repression of this network by the cilium. Cilium-ablated cells also exhibit features of activation including enhanced activity of Wnt and mitogen signaling, and elevated protein synthesis via inactivation of the translational repressor 4EBP1. Taken together, our results show that the primary cilium integrates and dampens proliferative signaling, represses translation and G2/M genes, and is integral to the establishment of the quiescence program.\n\nSummary statementThe primary cilium contributes to reversible arrest (quiescence) in skeletal muscle myoblasts, by coordinating and dampening mitogenic signaling focused on a G2/M transcriptional program and protein synthesis.