IGF-1 activates a cilium-localized noncanonical Gβγ signaling pathway that regulates cell-cycle progression

Dev Cell. 2013 Aug 26;26(4):358-68. doi: 10.1016/j.devcel.2013.07.014. Epub 2013 Aug 15.

Abstract

Primary cilia undergo cell-cycle-dependent assembly and disassembly. Emerging data suggest that ciliary resorption is a checkpoint for S phase reentry and that the activation of phospho(T94)Tctex-1 couples these two events. However, the environmental cues and molecular mechanisms that trigger these processes remain unknown. Here, we show that insulin-like growth-1 (IGF-1) accelerates G1-S progression by causing cilia to resorb. The mitogenic signals of IGF-1 are predominantly transduced through IGF-1 receptor (IGF-1R) on the cilia of fibroblasts and epithelial cells. At the base of the cilium, phosphorylated IGF-1R activates an AGS3-regulated Gβγ signaling pathway that subsequently recruits phospho(T94)Tctex-1 to the transition zone. Perturbing any component of this pathway in cortical progenitors induces premature neuronal differentiation at the expense of proliferation. These data suggest that during corticogenesis, a cilium-transduced, noncanonical IGF-1R-Gβγ-phospho(T94)Tctex-1 signaling pathway promotes the proliferation of neural progenitors through modulation of ciliary resorption and G1 length.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle / drug effects*
  • Cell Proliferation / drug effects
  • Cilia / drug effects
  • Cilia / metabolism*
  • Dyneins / metabolism
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Mice
  • Mitogens / pharmacology
  • Models, Biological
  • Neocortex / cytology
  • Neocortex / drug effects
  • Neocortex / embryology
  • Neocortex / metabolism
  • Phosphorylation / drug effects
  • Receptor, IGF Type 1 / metabolism
  • S Phase / drug effects
  • Signal Transduction / drug effects*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism

Substances

  • DYNLT1 protein, human
  • Dynlt1b protein, mouse
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Mitogens
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Dyneins