Thursday, May 27, 2010

Development of Hands and Wings: Protein Pentagone Important

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ScienceDaily (May 14, 2010) — Whether we are talking about our own hand or something seemingly so distant from an evolutionary perspective as the wings of an insect: In order to make an organ out of a multitude of cells, the cells have to know where they are during the development of the still growing organ. Cells use this information to decide whether, for instance, they will later become a part of the thumb or the pinky finger. It has long been known that cells receive information on their position as well as growth stimuli from signaling molecules present in the cell tissue, so-called morphogens -- real jacks of all trades, which are put to work again and again in the course of development. They are only produced by a small group of cells and have the ability to spread across the cell tissue in the form of a concentration gradient.

As signaling molecules, morphogens can switch genes on or off, even in distant cells. The decisive factor is that morphogens can regulate the activity of different genes depending on their concentration. In this way, they help to produce different gene products which determine which part of an organ will develop in each region during development.

In order to do this, morphogens need to be able to move around in the tissue while at the same time fulfilling their role as signaling molecules. They achieve the latter by binding to receptors, where they switch genes on and off. Since morphogens cannot spread any further once bound to receptors, there must be regulatory mechanisms which counter the effect of the receptor binding but do not completely inhibit the signaling.

A research team led by Dr. Georgios Pyrowolakis from the Institute of Biology I has discovered a mechanism of this kind in a study conducted on the fruit fly drosophila melanogaster. The results of the study have now been published in an article entitled "Control of Dpp Morphogen signalling by a secreted feedback regulator" in the online version of the journal Nature Cell Biology. The contributors to the study are Dr. Robin Vuilleumier, Alexander Springhorn, Stefanie Koidl, and Dr. Giorgos Pyrowolakis from the Institute of Biology I of the University of Freiburg as well as Prof. Dr. Markus Affolter from the Biozentrum in Basel and Prof. Dr. Matthias Hammerschmidt and Dr. Lucy Patterson from the University of Cologne.

The scientists conducted experiments on the wing precursor of the fruit fly, in which a morphogen called „Dpp" is active. They discovered the extracellular protein pentagone, which helps Dpp to spread and maintain the balance between mobility and receptor binding. If pentagone is not available, Dpp remains close to where it was produced and is involved more intensively in the signaling process. This leads to defective growth and the loss of parts of organs.

Interestingly, Dpp switches off the gene coded for pentagone directly through signaling. Pentagone is thus only produced in cells which are distant enough from the region in which Dpp is produced. It then spreads out toward the Dpp source, helping Dpp to gain mobility by way of an interaction with the extracellular matrix. As the authors were able to demonstrate in their experiments, the negative regulation of the pentagone genes is essential for the correct formation of the Dpp gradients. Moving the pentagone synthesis to other regions of the wing precursor and thus separating it from the Dpp signaling will lead to disproportions in the wings.

So why does the Dpp switch off the genes which help it to be mobile and effective over long distances? This tactic could be the key to the robustness of a gradient which needs to be in the position to counteract any fluctuations that may occur in the morphogen production rate or mobility during organ development. Too much Dpp would lead to less pentagones and thus to decreased mobility of the morphogen. A shortage of Dpp, on the other hand, would result in increased pentagone production but would be compensated by the resulting increase in Dpp mobility. This would mean that cells are equipped with a system which allows them to monitor the form of the morphogen gradient continuously and correct irregularities. Initial evidence points to an evolutionary conservation of this system.

Journal Reference:
Vuilleumier et al. Control of Dpp morphogen signalling by a secreted feedback regulator. Nature Cell Biology, 2010; DOI: 10.1038/ncb2064


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