Functional and mechanistic investigation of fish Stanniocalcins: From hypocalcemic hormone to local IGF signaling regulators

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

This project advances understanding of the glycoprotein hormone stanniocalcin, which is involved in regulating calcium concentrations in vertebrates. Calcium is an essential ion and plays key roles in a wide range of biological processes. The levels of calcium ion in the blood are tightly regulated by several hormones. The first stanniocalcin (Stc1) was discovered in fish in the 1960s, and recent advances in genomics have revealed that all vertebrates, including humans, have multiple stanniocalcin genes. Zebrafish, for instance, have 4 distinct stanniocalcin genes (stc1a, stc1b, stc2a, and stc2b). Genetic deletion of zebrafish Stc1a results in kidney stone formation, cardiac and body swelling, and premature death, but it is unclear how Stc1a loss leads to these defects. Moreover, the expression, regulation, and functions of Stc2a, Stc1b, and Stc2b are essentially unexplored. This project will determine whether impaired renal function in Stc1a-deficient animals leads to the accumulation of osmotic water and progressive development of cardiac edema and body swelling in zebrafish. The Stc1a receptor will be identified to gain an understanding of how Stc1a works at the molecular level. The expression, regulation and physiological functions of Stc1b, Stc2a, and Stc2b in gill and brain will also be investigated. The results should reveal novel insights on the physiological functions of stanniocalcin isoforms and their underlying mechanisms of action, and will fill a major gap in the field of comparative endocrinology. A mechanistic understanding of the role of stanniocalcins in brain, kidney, and gills should contribute to the development of new applications in the aquaculture industry. The research will incorporate training of undergraduate students and a post-doctoral fellow, contributing to workforce development. The researchers will develop a hands-on research activity for a K-12 summer camp in collaboration with the University of Michigan Museum of Natural History, using the zebrafish mutant lines developed in the project to teach the participants about hormones and calcium homeostasis. Stanniocalcin 1 (STC/Stc 1) was discovered in bony fish as a hypocalcemic hormone over half a century ago. Recent studies suggest that all vertebrates, including humans, have multiple STC/stc genes. In zebrafish, which have 4 stanniocalcin genes (stc1a, stc1b, stc2a, and stc2b), loss of Stc1a results in kidney stone formation, cardiac and body edema, and premature death. Mechanistically, Stc1a regulates ionocyte proliferation and calcium uptake by suppressing local insulin-like growth factor (IGF) signaling. However, the molecular identity of STC1/Stc1 receptor(s) is currently unknown in zebrafish or any other vertebrate. Furthermore, the expression, regulation, and functions of stc2a, stc1b, and stc2b are largely unexplored. This project tests the hypothesis that Stc1a, mediated by its binding to the cell surface-tethered metalloproteinase Papp-aa and/or the multi-ligand endocytosis receptor Megalin, regulate ionocyte proliferation, calcium uptake, and kidney function, while the other three stanniocalcins function locally in the brain and gills via context-dependent mechanisms. Specifically, the research will determine (1) whether Stc1a plays dual roles in ionocyte proliferation and calcium uptake by regulating local IGF signaling and epithelial calcium channel Trpv6 expression; (2) whether loss of Stc1a impairs renal function, leading to osmoregulation imbalance and body edema; (3) the molecular identity of Stc1a receptor(s); (4) the roles of Stc1b and Stc2a in brain growth and function; and (5) the possible role of Stc2a/2b in mediating hypoxia-induced growth reduction. The research will make conceptual contributions to the field of endocrinology. The project includes research training at multiple levels, including a Research Experiences for Undergraduates component. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.