Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma

Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9151-6. doi: 10.1073/pnas.1323265111. Epub 2014 Jun 9.


The primary cilium acts as a cellular antenna, transducing diverse signaling pathways, and recent evidence suggests that primary cilia are important in development and cancer. However, a role for cilia in normal muscle development and rhabdomyosarcoma (RMS) has not been explored. Here we implicate primary cilia in proliferation, hedgehog (Hh) signaling, and differentiation of skeletal muscle cells. Cilia and Hh signaling are highly dynamic during the differentiation of myoblasts. We show that cilia are assembled during the initial stages of myogenic differentiation but disappear as cells progress through myogenesis, concomitant with the destruction of proteins critical for cilia assembly and shortly after the Hh effector, Gli3, leaves the cilium. Importantly, we show that ablation of primary cilia strongly suppresses Hh signaling and myogenic differentiation while enhancing proliferation. Interestingly, our data further indicate that both cilia assembly and Hh signaling are deregulated in RMS, and cilia respond to Hh ligand in certain subsets of RMS cells but not others. Together, these findings provide evidence for an essential role for both primary cilia assembly and disassembly in the control of Hh signaling and early differentiation in muscle cells. We suggest that the temporally orchestrated destruction of centrosomal and ciliary proteins is a necessary antecedent for removal of the primary cilium and cessation of Hh signaling during myogenic differentiation. Additionally, our results further stratify RMS populations and highlight cilia assembly and disassembly as potential RMS drug targets.

Keywords: centrosome; ciliogenesis; myotube.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line, Tumor
  • Cilia
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Myoblasts, Skeletal / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / metabolism*
  • Signal Transduction*


  • Hedgehog Proteins
  • Neoplasm Proteins