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The two sides of a cell

Almost all cells are asymmetric – this is why for example the intestines, the brain and lungs function so well. Tumour diseases show why it is so important for a cell to have two different sides, a “head” and a “foot”. In cancer, genes that are responsible for the correct development of cell polarity are often defective. Dr. Felix Loosli from the Karlsruhe Institute of Technology investigates epithelial cells in the retina of the small Japanese medaka fish and zebra fish. Which molecular mechanisms establish the ordered development of the two cell poles? And what happens if this no longer functions properly?

Cross-section through an eye of a fish larva: the retinal cells are arranged close to each other and form an ordered layer. This is another good example of an epithelium. © Dr. Felix Loosli

Cells of the epithelial layers and organs need to have two different sides. The example of the intestines shows why this is the case: directly at the border to the interior of the intestines, the epithelial cells are closely connected with each other through push-button-like protein complexes that cement the intestinal wall together. The epithelial cells also have structures that enable them to selectively take up nutrients into the cells' interior. The nutrients migrate through the cell in order to reach the blood on the other side of the epithelium. There, i.e. at the "foot", the nutrients are transferred into the blood vessels with the help of other protein complexes. Without this polar specialisation, the content of the intestines would seep uncontrollably into tissue and blood. "Which molecular mechanisms ensure that the two sides of an epithelial cell are so different?" is the question asked by Dr. Felix Loosli, independent group leader at the Institute of Toxicology and Genetics at the Karlsruhe Institute of Technology (KIT).

Gaining a better understanding of the network

There are three groups of molecules that control the polarity of cells; these groups are found in the intestines, the lungs and all other organs. The first group consists of adhesion molecules that protrude the membrane and tightly fuse neighbouring cells with each other. These molecules anchor the cells in the tissue and enable cell-cell contacts. The second group, which are signalling molecules, are found inside the cells. These signalling molecules translate information from the tissue into a cell response. These molecules trigger cells to form structures at their “head” that are different from those at their “foot”. The two groups are linked by scaffold proteins that also establish links with the cytoskeleton. The cytoskeleton determines the morphology of the cells and also enables targeted cell movements in the tissue, something that is important for patrolling immune cells. Loosli and his team have taken on the task of gaining deeper insights into the network that consists of different molecular players. “Cell polarity is already of great importance in the early development of an organism,” said the biologist. “Cell polarity defects lead to the malformation of organs.”

In addition, defects in the genes encoding the three protein classes are often associated with cancer. If the cells lose their signalling antennae, they are unable to react to braking influences from the environment, and continue to divide, eventually becoming tumour cells. If they also lack a certain adhesion molecule, they start to migrate and can form metastases in other parts of the body. Loosli started his research in Jochen Wittbrodt’s work group at the EMBL in Heidelberg. Back then, he was investigating the polarity of cells of the developing nervous system and has since used fish retinas as a model system, i.e. the retina of the small Japanese medaka fish and of zebra fish. “The retinas of these two fish species are excellently suited for experimental approaches,” said Loosli. “They have a very simple architecture, which is the same in all vertebrates, including humans.” The fish embryos develop outside of the mother. The transparency of the fish embryos enables Loosli and his team to use modern microscopy and staining methods to investigate the development of individual cells and cell groups in real time and in the living embryo. In addition, they can also alter individual genes with simple means.

An important regulator of cell polarity

Fish embryo seen from above, the head is on the left. The fluorescence originates from a GFP-labelled protein that only occurs in the upper regions of cells. This image shows that the cell polarity is not faulty. © Dr. Felix Loosli

Loosli and his team focus mainly on the functional alteration of the genes. The scientists use a chemical to introduce mutations into the fish genes, thereby impairing gene function. This provides them with insights into changes in cell polarity. They can see the changes by making proteins that are known to be responsible for the asymmetric division of cells visible. The researchers couple proteins to a second, small fluorescent protein that fluoresces in living tissue (GFP, green fluorescent protein). When the cells are looked at under the microscope, the researchers normally only see the "foot" of the cells fluorescing. If however, the function of relevant genes is defective due to mutations, then the proper distribution of GFP is impaired, and the cells fluoresce everywhere. This method provides Loosli and his team with a sensor that indicates cell polarity disorders in living fish.

Cross-section through an eye of a fish larva whose cell polarity gene is mutated: the cells of the retina no longer form an epithelium, arranging themselves instead in a chaotic manner. © Dr. Felix Loosli

Some time ago, Loosli discovered a gene that affects cell polarity. The gene product appears to be an important regulator of signalling proteins. Loosli called this gene "medeka", alluding to the Japanese meaning of the fish's name. Medaka means "small animal with big eyes". Changing the "a" with an "e" shifts the meaning towards "big eye", in reference to the fact that the mutants have enlarged organs of vision. The retina does not develop correctly, the cells do not adhere to each other correctly and pure chaos results in the tissue.

At present, Loosli and his team are investigating the signalling proteins that are influenced by this regulator. Why is the activity of these signalling proteins important for the development of cell polarity? With which known molecules does the regulator also interact? "We would like to add another component to the already known network in the hope that this will enable us to better understand these processes," said Loosli. In addition, the researchers are also looking for similar proteins in mammals, including mice and humans. The next project however involves the comprehensive genetic screening of the fish genome. Loosli and his group of researchers hope to find additional genes that affect cell polarity in the retina. Using a new illumination sensor, the process of identifying further genes is much simpler than when Loosli first started this type of work. The project is carried out in cooperation with many other research groups. "We are now able to investigate a large number of fish eggs," said Loosli. Therefore, progress can soon be expected in the field of cell polarity research.

Further information:

Dr. Felix Loosli
Karlsruhe Intitute of Technology (KIT)
Institute of Toxicology and Genetics
Tel.: +49-(0)7247/82-8743
Fax: +49-(0)7247/82-3354
E-mail: felix.loosli(at)kit.edu

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/the-two-sides-of-a-cell