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

   https://doi.org/10.3389/fcell.2021.662915  

   Li, Shuang; Liu, Chengdong; Goldstein, Allison; Xin, Yi; Ke, Caihuan; Duan, Cunming (April 2021, Frontiers in Cell and Developmental Biology)

   Yao, Guang (Ed.)

   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). Zebrafishstc1a, but not the otherstcgenes, is expressed in a Ca²⁺state-dependent manner. Genetic deletion ofstc1a, but notstc2b, 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 instc1a^–/–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 ofpapp-aaor its substrateigfbp5ain thestc1a^–/–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. 

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2. The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

   https://doi.org/10.7554/eLife.52322  

   Liu, Chengdong; Li, Shuang; Noer, Pernille Rimmer; Kjaer-Sorensen, Kasper; Juhl, Anna Karina; Goldstein, Allison; Ke, Caihuan; Oxvig, Claus; Duan, Cunming (April 2020, eLife)

   Ackert-Bicknell, Cheryl (Ed.)

   Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress. 

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3. FK506 ‐binding protein 5 regulates cell quiescence‐proliferation decision in zebrafish epithelium

   https://doi.org/10.1002/1873-3468.14670  

   Li, Yingxiang; Liu, Chengdong; Bai, Xuanxuan; Li, Mingyu; Duan, Cunming (June 2023, FEBS Letters)

   Using a zebrafish ionocyte model, transcriptomics and genetic analyses were performed to identify pathways and genes involved in cell quiescence‐proliferation regulation. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyses revealed that genes involved in transcription regulation, cell cycle, Foxo signalling and Wnt signalling pathway are enriched among the up‐regulated genes while those involved in ion transport, cell adhesion and oxidation–reduction are enriched among the down‐regulated genes. Among the top up‐regulated genes is FK506‐binding protein 5 (Fkbp5). Genetic deletion and pharmacological inhibition of Fkbp5 abolished ionocyte reactivation and impaired Akt signalling. Forced expression of a constitutively active form of Akt rescued the defects caused by Fkbp5 inhibition. These results uncover a key role of Fbkp5 in regulating the quiescence‐proliferation decision via Akt signalling. 

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4. Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

   https://doi.org/https://doi.org/10.7554/eLife.48003.001  

   Yi Xin, Allison Malick (September 2019, eLife)

   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. 

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5. Stanniocalcin 1a regulates organismal calcium balance and survival by suppressing Trpv6 expression and inhibiting IGF signaling in zebrafish

   https://doi.org/10.3389/fendo.2023.1276348  

   Li, Shuang; Li, Helena; Wang, Zhengyi; Duan, Cunming (October 2023, Frontiers in Endocrinology)

   Stanniocalcin 1 (Stc1) is well known for its role in regulating calcium uptake in fish by acting on ionocytes or NaR cells. A hallmark of NaR cells is the expression of Trpv6, a constitutively open calcium channel. Recent studies in zebrafish suggest that genetical deletion of Stc1a and Trpv6 individually both increases IGF signaling and NaR cell proliferation. Whiletrpv6^-/-fish suffered from calcium deficiency and died prematurely,stc1a^-/-fish had elevated body calcium levels but also died prematurely. The relationship between Stc1a, Trpv6, and IGF signaling in regulating calcium homeostasis and organismal survival is unclear. Here we report that loss of Stc1a increases Trpv6 expression in NaR cells in an IGF signaling-dependent manner. Treatment with CdCl₂, a Trpv6 inhibitor, reduced NaR cell number instc1a^-/-fish to the sibling levels. Genetic and biochemical analysis results suggest that Stc1a and Trpv6 regulate NaR cell proliferation via the same IGF pathway. Alizarin red staining detected abnormal calcium deposits in the yolk sac region and kidney stone-like structures instc1a^-/-fish. Double knockout or pharmacological inhibition of Trpv6 alleviated these phenotypes, suggesting that Stc1a inhibit epithelial Ca²⁺uptake by regulating Trpv6 expression and activity.stc1a^-/-mutant fish developed cardiac edema, body swelling, and died prematurely. Treatment ofstc1a^-/-fish with CdCl₂or double knockout of Trpv6 alleviated these phenotypes. These results provide evidence that Stc1a regulates calcium homeostasis and organismal survival by suppressing Trpv6 expression and inhibiting IGF signaling in ionocytes. 

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