Figure 9.

A proposed model on how Trpv5/6 regulates IGF signaling and epithelial growth under normal and Ca²⁺-deficient conditions. Upper panel: under normal [Ca²⁺], the activity of IGF1R-PI3K-Akt signaling in NaR cells is under the negative regulation of Trpv5/6 and cell proliferation is kept at low levels. As a result, there are a limited number of NaR cells on the larval yolk sac skin. Lower panel: under low [Ca²⁺] environments, the number and density of NaR cells increase dramatically due to elevated proliferation of pre-existing NaR cells. Low [Ca²⁺] results in changes in Trpv5/6 activity (1). This leads to membrane depolarization (2), which in turn leads to the amplification of IGF signaling at the levels of PI3K and Akt (3). Local Igfbp5a facilitates the IGF ligand and receptor binding (4). The activation of IGF1R-PI3K-Akt signaling stimulates NaR cells to re-enter the cell cycle (5), leading to the increased NaR cell number and density