Scale models

Weizmann Institute scientists have added a significant piece to the puzzle of scaling – how patterns stay in sync with size as an embryo or organism grows and develops. In a new study appearing in Current Biology, Institute scientists Profs. Naama Barkai and Ben-Zion Shilo and research student Danny Ben-Zvi of the Molecular Genetics Department have shown how scaling works in developing fruit fly wings – in which the vein structure stays perfectly proportioned – and their findings should be applicable to many different examples of development, including human embryonic development.

The scientists knew that patterning relies on morphogens – substances that are secreted by a small number of cells in the center of the developing embryo, and from there, diffuse outward. As morphogens disperse, the levels drop off in the cells further from the center, and thus the concentration relays a signal to the developing cells about their place and function in the growing organism. But such a morphogen diffuses from the center at the same rate in a small organism as in a larger one, and thus would not effect scaling on its own.

Several years ago, the researchers found a molecule in frog embryos that is synthesized at the edges and diffuses inward. This second molecule also functions as a morphogen, and it is the redistribution of this molecule that finally determines the morphogen signal each developing cell receives, in a way that takes embryo size into consideration.

Next, Barkai and Ben-Zvi created a theoretical model, called an expansion-repression model, in which an expander molecule on the growing edge aids in the distribution of the central morphogen, which eventually represses the synthesis of the expander molecule at the edge. The model suggests just how this interplay between expansion created at the edge and repression moving from the center results in a pattern built to scale.

Ben-Zvi, Barkai and Shilo have now brought the theoretical model back into the lab, carrying out experiments on fruit fly larvae, in which wing patterning already begins in small structures called wing discs.

The scientists collected fruit fly larvae of varying sizes and, using a quantitative method they developed, checked the distribution of concentrations of a morphogen called Dpp. Then, they eliminated another molecule called Pentagone – which they suspected of playing the role of expander – from the developing wing disc and checked again. Their findings showed that the wings in the unaltered fruit flies revealed the morphogen scaling activity predicted by the model, its signals being proportionate to wing size. In contrast, in the flies without Pentagone the Dpp morphogen was distributed in the same way in all the wings, regardless of their relative sizes. Thus, they were able to show that Pentagone is, indeed, an expansion molecule and that the expansion-repression paradigm they had formulated can be applied to such differing organisms as frogs and fruit flies.

Shilo said: "The beauty of this research lies in the way it seamlessly weaves a theoretical model into experimental biology. With this fresh, new approach to investigating scaling, rather than searching for complex molecular mechanisms, we can begin by looking for this relatively simple and universal paradigm."

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