Identifying the mechanisms through which calcineurin regulates proportional growth control.

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All organisms grow organs and appendages to specific proportions in relation to their bodies, and those animals that regenerate them do so to the exact same dimensions as the lost original structures. The coordinated growth of organs and appendages during development and regeneration involves switching between growth rates that are disproportional to the body (allomentric) and growth rates that are proportional the body (isometric). While many aspects of the cell biology, hormone, growth factor and cell cycle regulation contribute to the cell proliferation associated with tissue growth are known, it remains unclear how these mechanisms are coordinated to produce proportional growth of organs and appendages relation to the body. My group discovered that inhibition of the calcium-regulated phosphatase calcineurin during the regeneration of zebrafish fins causes their loss of proportional growth control and that calcineurin inhibition in unamputated fins switched their isometric growth to allometric growth. While it is known that there are body-wide and local regulators of growth control, it is not known how these are regulated or integrated to control proportional growth of multi-tissue structures. Therefore, the goal of my Eigene Stelle (Temporary PI) proposal is to define how the calcium-regulated phosphatase calcineurin is integrated into the cell biology and molecular mechanisms that determine when tissue progenitor cells are to grow and to stop growing to maintain the proportional relationship to the body. To achieve this goal, I will determine: 1) which cell(s) mediates calcineurin-regulated of proportional growth; 2) what downstream molecular mechanisms mediate calcineurin-regulated proportional growth; 3) which molecular mechanisms (both Ca2+-mediated and Ca2+-independent) are regulating calcineurin to regulate proportional growth.