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MORPHOGEN Report Summary

Project ID: 339105
Funded under: FP7-IDEAS-ERC
Country: Switzerland

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

Morphogen are secreted signaling molecules that are deployed as gradients of concentration in developing tissues. Morphogen gradients control patterning and growth during development. We have previously showed that spatial morphogen gradient scale with the size of growing tissue. Gradient scaling mediates an ever increasing concentration of the morphogen in the cells of the tissue. We showed that this increase of concentration over time is measured by cells (i.e. C ̇/C, the time derivative of concentration C ̇ normalized to the concentration C), which thereby use this information to determine the growth rate, the time it takes for a cell cycle. We have study two key factors which control this expansion of the gradient: the secreted molecule Pentagone and the extracellular Heparane Sulfate Proteoglycan Dally.
We are studying the physics and molecular cell biology of scaling and C ̇/C growth control using two working hypotheses as framework: i) scaling is mediated by specific expander molecules (Dally and Pentagone) which interact with Dpp and control its sorting into two distinct endocytic routes (the Clathrin versus the GEEC pathway) and ii) computation of C ̇/C is mediated by a Negative Feed-Back Loop with a buffering Node (NFBLB) which wires Dpp signaling with two other key growth controling pathways: Myc and Hippo/Yorkie. Our approach is an interdisciplinary combination of physical theory, biophysics and molecular cell biology in the context of embryogenesis and development in Drosophila and Zebrafish.
At this point of the project, we have established a plethora of assays, reagents and theoretical frameworks as planned in our proposal. In particular, we achieved already the development of many of the novel and unconventional methodologies that we proposed. This includes the Dpp fluorescent timers and the nanobody uptake assay, both of which allow us to measure the kinetic parameters of the transport of Dpp in the tissue and the trafficking of Dpp inside cells.
Also remarkably, we have already advanced considerably in our theoretical understanding of Dpp transport and the assays to study it. In particular, we found that Dpp transport can be best captured by an eigen mode structure approach, a strategy which has been very succesful in the study of physical systems, a prominent case of which is hydrodynamics. This is characterized by different time scales (“frequencies”) and length scales. Biologist have somehow a “fuzzy” intuition of these times scales, but an eigen mode approach rationalizes this, and allow us to design assays at different time and length scales with a full mathematical awareness of the implications behind the different eigen modes. This is really a new way of doing science for biology.
We have generated almost all the reagents (in particular, fly lines) in our plan. We achieve this very efficiently. This was in part possible because we jump very early in the CRISPR revolution, which allow gene editing: tagging the endogenous genes with fluorescent proteins. We have tagged at endogenous levels the two scaling factors, Dally and Pentagone, and integral components of the Dpp pathway, including Dpp itself, the receptor thickveins, and the target gene Dad.
We have study a minimal culture system to study derivative computation by NFBLB. We now moved in vivo, and found that Hippo pathway mutants are mutants in the derivative computation. In fish, we have now established that the Dpp homolog pathway, BMP also shows gradient scaling in the growing pectoral fin. A mutant for the fish ortholog of Pentagone shows a scaling phenotype.
A number of manuscripts on these issues are in advanced preparation phase.

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