Examining the mechanism of the gene simplet (smp) in nerve-dependent appendage regeneration of the zebrafish
Final Report Abstract
From the funding of this grant, we made two major discoveries: One, we identified Smp as a regulator of β-catenin-dependent Wnt signaling. Two, we identified calcineurin as a regulator of proportional growth control of zebrafish appendages. The first discovery opens new avenues to understand how Wnt signaling is regulated and how calcineurin coordinates control of regenerative growth. Because Smp regulates β-catenin nuclear localization, this discovery leads to further exploration on what regulates Smp to regulate β-catenin. In addition to β-catenin, Smp may also regulate the nuclear localization of other factors. Mass spectrometry experiments can determine what proteins are regulating Smp and what factors are shuttling between the cytoplasm and the nucleus with Smp. Furthermore, and β-catenin-dependent signaling is involved in the progression of many cancer types; therefore, human SMP could be target for the design of new pharmaceutical agents to treat cancer. The second finding that two clinically approved calcineurin inhibitors (used as immunosuppressants in patients) enhance regenerative outgrowth in part through the upregulation of retinoic acid provides avenues for further discoveries in the cell and molecular biology of overarching controls of multi-tissue coordinated proportional growth. In particular, subsequent questions we will address are 1) how calcineurin is regulating retinoic acid signaling, 2) which cells are involved in mediating calcineurin’s regulation of regenerative growth and 3) whether the calcineurin inhibitors act through signaling pathways other than retinoic acid.
Publications
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“Regeneration of Organs and Appendages in Zebrafish: A Window into Underlying Cellular and Molecular Control Mechanisms”, Wiley-Blackwell (2010), Encyclopedia of Life Sciences
Antos CL and Brand M
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“Vertebrates that Regenerate as Models for Guiding Stem Cells” in The Cell Biology of Stem Cells, Eds. Meshorer E & Plath K, Landes Bioscience. Landes Bioscience (2010) Advances in Experimental Medicine and Biology Vol. 695: 184-214
Antos CL and Tanaka EM
