How the Pentagone protein controls development
How do the cells in a human embryo know their current location or where to go next? Why do certain cells form a finger, but not others? University of Freiburg biologists in Germany believe the protein Pentagone controls these steps in the fruit fly — and perhaps in humans as well.
According to University of Freiburg biologist Dr. Giorgos Pyrowolakis, the proteins Dpp and Pentagone are crucial for a developmental step in the organism of wings of the fruit fly Drosophila melanogaster. However, the same proteins are also present in a similar form in humans.
The fundamental principles elucidated in this study are also active in humans, where they might control things like where cells form fingers," says Dr. Pyrowolakis. He adds: "In the future, these results could contribute to our understanding of the origin of developmental disorders."
Pyrowolakis along with Jennifer Gawlik, Dr. Mark Norman, Alexander Springhorn, and Robin Vuilleumier published their findings in the journal eLife.
Cells located in the middle of the future wing produce Dpp which then spreads to the rest of the cells in the tissue, becoming less concentrated as it disperses. In mathematical terms, this process is known as a concentration gradient. Genes are activated depending on where they are located in this gradient. For example, veins develop when specific protein concentrations are reached. So, the distance between the veins on a fruit fly's wing are determined by the Dpp concentration gradient.
Cells farthest from the Dpp source produce Pentagone. Without Pentagone, there would be no Dpp concentration gradient in the cell network and Dpp would not function past its point of origin.
Image Credit: Martin Hauser, California Department of Food and Agriculture
If the Pentagone gene is switched off in fruit flies, the insect's wings are smaller and its external vein missing.
Dpp binds to receptors on the surface of the cell of the future wing, initiating a signal cascade. This signal burst activates genes to bind to Dpp via a co-receptor which then passes Dpp on to the receptor.
Pentagone then causes co-receptors to be absorbed into the cell where they are broken down, which reduces the amount of co-receptors and likewise reduces Dpp. With less Dpp, receptors become less active.
"When the wing grows, the Dpp gradient expands. Pentagone regulates the gradient in a similar way a thermostat adjusts temperature."
George Pyrowolakis PhD, Centre for Biological Signalling Studies, Albert-Ludwigs-University of Freiburg, Breisgau, Germany; Institute for Biology I, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated.
Giorgos Pyrowolakis is a research group leader at the Institute of Biology I, Department of Developmental Biology, of the University of Freiburg, a member of the Freiburg Cluster of Excellence BIOSS Centre for Biological Signalling Studies, and a principal investigator at the Spemann Graduate School of Biology and Medicine (SGBM). Jennifer Gawlik is a member of his research group and a member of the SGBM. Robin Vuilleumier and Alexander Springhorn are former members of Pyrowolakis's research group. Springhorn was also a member of the SGBM. The primary author of this study, Mark Norman, was a postdoctoral researcher in the group. His project was funded by BIOSS.
Original publication: Mark Norman, Robin Vuilleumier, Alexander Springhorn, Jennifer Gawlik, Giorgos Pyrowolakis (2016). Pentagone internalises glypicans to fine-tune multiple signalling pathways. eLife. DOI: 10.7554/eLife.13301
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Jul 5, 2016 Fetal Timeline Maternal Timeline News News Archive
(RED) Co-receptors located on the surfaces of cells.
(YELLOW/GREEN) Pentagone degrading and internalizing Dpp.
Image Credit: Research Group Pyrowolakis