Researchers from Johns Hopkins University have revealed, with the help of computer models and living cells, a unique pattern capable of guiding cell movement
Researchers have shown through computer models and research in living cells that cell migration is caused, among other things, by a struggle between two proteins. This kind of migration is involved in the creation of many patterns in nature.
The stripes of the zebra, the spiral of the sea snail, the wings of the butterfly: these are all examples of patterns in nature. How are those patterns created? This mystery charms and bewitches mathematicians and biologists alike. How does the delicate model of the butterfly's wings form, from a single fertilized egg?
Researchers from Johns Hopkins University have revealed, with the help of computer models and living cells, a unique pattern capable of guiding cell movement. The study was published in the May issue of the scientific journal Developmental Cell, and may help us understand how cancer cells metastasize and move around the body.
"Pattern formation is a classic problem in embryology," says Dr. Denise Montal, a professor of biological chemistry at Johns Hopkins. "At some point, the cells in the embryo must divide into those that will become heart cells, liver cells, blood cells, and so on. Although this has been studied for years, there is still much we do not understand."
As an example of creating a pattern, the researchers examined a process that occurs in the fruit fly, in which six cells separate from all their members and move from one place in the ovary to another place during the development of the egg.
"For this cell migration to occur, there have to be cells that go and cells that stay," Montal says. "There must be a clear differentiation, a separation between different types of cells that look identical on the surface."
Previous work has identified a specific signal that is needed to make the fly eggs move. The problem is that this signal is scalable, and changes depending on place and time. It starts at a high level in the adjacent cells, but gets weaker as it moves away from them. The signal can be compared to a single drop of paint dripping into a glass of water. The color is strong in the original drop, but it spreads in the solution quickly, until the entire glass is filled with very thin color. The signal functions in a different way, but has an effect only when it exists at a certain level.
In order to create patterns, sharp and clear boundaries are necessary - there are no gray areas between the white and black stripes of the zebra. That is why it is not possible to be satisfied with only one signal whose level changes with time and place. How, then, do such signals convey the instruction to the cells - to go or stay? To answer the question, the researchers examined flies with mutations in various genes, and discovered that one gene in particular, called apontic, is particularly important for converting the scalable signal.
"When the apontic is mutated, the distinction between the migratory and non-migratory cells is blurred," says Michelle Startz-Gaiano, a postdoctoral researcher in biological chemistry. "In these mutants we see many cases where migrating cells do not separate properly from their neighbors, but drag them along with them when they move." This phenomenon, according to the researchers, showed that the scaling signal by itself is not enough to drive the correct number of cells, and that it needs help from the apontic shield.
After the group discovered that the pontine was important for cell movement, they began to try to understand how it worked. In collaboration with the mathematician Hans Meinhardt, professor emeritus from the Max Planck Institute in Germany, they designed a computer model that could simulate how graded signals are transduced into commands and instructions for the cells.
The group made certain assumptions regarding each gene and the role of each protein, and created a simple computerized circuit capable of predicting the behavior of a cell according to the graded signal it receives, and relying on the activity of the aphontic gene and another protein called slbo that was recently discovered. The computer model shows that the graded signal activates both the aphontic and the slobo in the cell, but the harmony stops there. The aphontic and the slobo work against each other and struggle with each other. When one gets a small advantage, the other weakens and thus makes the first even stronger. This chain of events continues until one of them takes over each cell completely. If the slob wins, the cell moves. But if the hapnotic wins, the cell remains stationary. In this way, a clear separation is obtained between the command to move or to stay.
"Not only is this a new solution to the problem of pattern formation from disorder, but we also discovered that ephnotics serves as a new controller of cell migration," Montal says.
Most likely, the ability of cells to migrate provides the basis for the spread of cancer cells outside the original tumor and to other areas of the body. Understanding the mechanisms that the cells use to migrate may provide us with a powerful tool to prevent the formation of metastases in tumors. Is there new hope here? It is possible, but there is no doubt that this hope will involve many more years of research. All Schmontel is willing to say at this point is that, "It's a lot more than just understanding what the positive and negative controls of cell migration are."
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A deep article, which will be discussed a lot later.