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Morphogenetic growth control by time derivatives of signaling

Final Report Summary - MORPHOGEN (Morphogenetic growth control by time derivatives of signaling)

During this project we have studied the mechanisms of generation of a morphogen gradient. Morphogen are secreted molecules which are produced in a region within a developing tissue and diffuses from there to generate a gradient of concentration through out the organ. Cells can compute the concentration of the morphogen to express different target genes and thereby acquire positional information. This positional information is used to differentiate disctinct structures in the organ at stereotyped, precise positions. The same morphogen molecules are used to control the growth of the tissue. We found before we started this project that growth control is mediated by a mechanisms in which cells can compute the time derivative of the morphogen concentration i.e. the fold increase of morphogen concentration. Indeed, the concentration of the morphogen in a cell increases as the tissue grows. The reason for this increase of concentration is that the morphogen gradient scales. Scaling means that the range of the gradient (how far it reaches from the source into the target tissue) remains proportional to tissue size. In the project, we aimed at studying the scaling process using the wing of the drosophila flies and the pectoral fin of zebrafish as model systems.
To achieve this, we undertook an approach at the interface between physics and biology. We develop a model based on theoretical physics and used this framework to design experiments which allow us to measure properties of the morphogen such as its diffusion and its destruction. We also looked at the trafficking inside cells to determine the precise route of spreading through the cells in the tissue. Once we understood the trafficking route we were ready to tackle the key question: what is that changes in the cells so that the morphogen reach can be longer and longer as the tissue grows. We found that what changes is the capability of cells to recycle the morphogen molecules that they have uptaken. We then study the machinery (the factors) behind those changes. These factors are molecules in the intercellular space, so called heparane sulfate proteoglycans and their binding proteins.
This was studied first in the wings of flies. We then looked in the pectoral fins of fish. There we found that the same principles apply. What we studied in the wings is not an oddity of flies, but seem correspond to universal principles during embryogenesis and development that are conserved from insects to vertebrates.