Abstract
Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here, we report that Trpv6, a cation channel responsible for epithelial Ca2+ absorption, functions as a key regulator of cellular quiescence. Genetic deletion and pharmacological blockade of Trpv6 promoted zebrafish epithelial cells to exit from quiescence and re-enter the cell cycle. Reintroducing Trpv6, but not its channel dead mutant, restored the quiescent state. Ca2+ imaging showed that Trpv6 is constitutively open in vivo. Mechanistically, Trpv6-mediated Ca2+ influx maintained the quiescent state by suppressing insulin-like growth factor (IGF)-mediated Akt-Tor and Erk signaling. In zebrafish epithelia and human colon carcinoma cells, Trpv6/TRPV6 elevated intracellular Ca2+ levels and activated PP2A, which down-regulated IGF signaling and promoted the quiescent state. Our findings suggest that Trpv6 mediates constitutive Ca2+ influx into epithelial cells to continuously suppress growth factor signaling and maintain the quiescent state.
Highlights
Quiescence is a non-proliferative cellular state found in many cell types in the body
The trpv6D7 and trpv6D8 lines were made in the Tg(igfbp5a:GFP) fish background
Whole-cell patch clamp experiments confirmed that the Trpv6 mediated Ca2+ current and this activity was abolished in the Trpv6D539A mutant (Figure 1H)
Summary
Quiescence is a non-proliferative cellular state found in many cell types in the body. Maintaining a pool of quiescent cells is critical for tissue repair, wound healing, and regeneration (Cheung and Rando, 2013). This is important for epithelia which are rapidly and continuously renewed throughout life. By synchronizing cultured mammalian cells in G0 via serum starvation followed by serum re-stimulation, Yao et al (2008) showed that the Rb proteins (pRb, p107, and p130) and their interactions with E2F proteins are critical in regulating the proliferation-quiescence decision (Yao et al, 2008). A bifurcation mechanism controlled by CDK2 activity and p21 regulating the proliferation-quiescence decision has been demonstrated in cultured mammalian cells (Spencer et al, 2013). The exceptionally high turnover rate implies that celltype-specific mechanism(s) must exist
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