Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

The molecular mechanisms regulating cell quiescence-proliferation balance are not well defined. Using a zebrafish model, we report that Stc1a, a secreted glycoprotein, plays a key role in regulating the quiescence-proliferation balance of Ca²⁺ transporting epithelial cells (ionocytes). Zebrafish stc1a, but not the other stc genes, is expressed in a Ca²⁺ state-dependent manner. Genetic deletion of stc1a, but not stc2b, increased ionocyte proliferation, leading to elevated body Ca²⁺ levels, cardiac edema, body swelling, and premature death. The increased ionocyte proliferation was accompanied by an increase in the IGF1 receptor-mediated PI3 kinase-Akt-Tor signaling activity in ionocytes. Inhibition of the IGF1 receptor, PI3 kinase, Akt, and Tor signaling reduced ionocyte proliferation and rescued the edema and premature death in stc1a fish, suggesting that Stc1a promotes ionocyte quiescence by suppressing local IGF signaling activity. Mechanistically, Stc1 acts by inhibiting Papp-aa, a zinc metalloproteinase degrading Igfbp5a. Inhibition of Papp-aa proteinase activity restored ionocyte quiescence-proliferation balance. Genetic deletion of papp-aa or its substrate igfbp5a in the stc1a background reduced ionocyte proliferation and rescued the edema and premature death. These findings uncover a novel and Ca²⁺ state-dependent pathway regulating cell quiescence. Our findings also provide new insights into the importance of ionocyte quiescent-proliferation balance in organismal Ca²⁺ homeostasis and survival.