AUTHOR=Li Shuang , Liu Chengdong , Goldstein Allison , Xin Yi , Ke Caihuan , Duan Cunming TITLE=Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.662915 DOI=10.3389/fcell.2021.662915 ISSN=2296-634X ABSTRACT=

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.