IGF-1 Activates a Cilium-Localized Noncanonical Gβγ Signaling Pathway that Regulates Cell-Cycle Progression

• DOI: 10.1016/j.devcel.2013.07.014
• Publication Date: 2013-08-15T13:28:38Z
• Authors: Celine Yeh; Aiqun Li; Jen-Zen Chuang; Masaki Saito; Alfredo Cáceres; Ching-Hwa Sung
• Keywords: Neocortex; Models, Biological; Receptor, IGF Type 1; S Phase; Mice; 03 medical and health sciences; GTP-Binding Protein gamma Subunits; https://purl.org/becyt/ford/3.1; Animals; Humans; https://purl.org/becyt/ford/3; Cilia; Insulin-Like Growth Factor I; Phosphorylation; Cell Proliferation; 0303 health sciences; Stem Cells; Igf1; Cell Cycle; GTP-Binding Protein beta Subunits; Dyneins; Señalización; Dineina; Mitogens; Developmental Biology; Signal Transduction

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.