Cadherins play an important role in cell adhesion by ensuring that cells within tissues are bound together. They prevent tumour cells from detaching from tumour tissue and migrating to other organs in the body to form new colonies. However, this is only one side of the coin. It has been known for some years now that cadherins can do just the opposite. Dr. Almut Köhler from the Karlsruhe Institute of Technology (KIT) and her group of researchers are investigating a cadherin type that is even able to actively promote cell migration in developing frog brains and tumour tissue.
The epithelium is a layer of cells that are bound so tightly to each other that nothing is able to pass through them. This is important in the intestines, for example, where substances that may pass through the intestinal wall into the blood need to be differentiated from those that must not. Membrane proteins of the cadherin family bind neighbouring cells of the epithelial layer together in a zip-like fashion. They are anchored in the cell membrane and extend into the extracellular space where they fit into the cadherins located in the membrane of neighbouring cells in the same way as a key fits into a lock. The adhesion of cells is crucial during embryonic development. Cells located in what is referred to as the cranial neural crest must remain together. Other cells, however, need to detach at the right point in time and migrate, for example in order to form what later become the eyes. “Researchers have long thought that cadherins have only one role, namely to promote the adhesion between cells,” said Dr. Almut Köhler from the Department of Cell and Developmental Biology at the Institute of Zoology of the Karlsruhe Institute of Technology (KIT).
Almut Köhler was born in 1971 in the Westphalian city of Schwelm, and studied veterinary medicine and did her doctorate at the German Federal Research Institute of Animal Breeding and Animal Behaviour (now Friedrich Löffler Institute) on the molecular development of the brain. She studied the effect hormones have on the gender differences of hatched chicken brains in a late phase of development. The frog Xenopus, which became Köhler’s model system when she moved to Karlsruhe in 2002, can be used to provide answers to research questions that cannot be answered using the chicken as model. This is due to the fact that frog eggs develop outside of the female body and have no eggshell. “Working with frogs provided me with experimental access to the very early developmental processes of nervous system development, and hence gave me insights into the migratory behaviour of cells,” said Köhler.
Almut Köhler initially concentrated on the development of the eyes, but was soon attracted by the protein cadherin-11, which was already a major research focus in her department. Her colleagues discovered cadherin in cells that leave the cranial neural crest during embryonic development. As the frogs mature, the neural crest develops into sensory neurons, connective tissue for sensory neurons as well as cartilage tissue of the head or dentin. It is only found in vertebrates. The question the researchers were seeking to answer was: what is the role of cadherin in cell migration? This is also an important question in clinical settings because cadherin-11 has been detected in cartilage and prostate tumour cells that migrate and form metastases.
Over the next few years, Köhler and her research group carried out experiments in cooperation with different partners in which they increased or prevented the expression of cadherin-11 in the neural crest cells of frog embryos in order to look at embryonic cell movements under fluorescent microscopes. The results of the study revealed a rather complex picture, which showed that cadherins are not only involved in cell adhesion, but also have other functions. The researchers found that very high cadherin-11 concentrations in the tissue made cells bind very closely to each other. However, when the researchers blocked the expression of cadherin using morpholino oligonucleotides, the cells of the cranial neural crest did not, as expected, migrate away. Instead they fidgeted on the spot.
Further research showed that newly produced cadherin-11 is normally transported into the cells’ filopodia, i.e. the projections that move backwards and forwards as the cells move towards their final destination. The filopodia are unable to find their way without cadherin-11. Cadherin-11 would therefore appear to be a molecule that has different effects.
As the group carried out further experiments, the cadherin picture became even more complex. The researchers found that the intracellular domain of cadherin is connected to a signalling network that is crucial for the early development of vertebrate embryos. This network is known as the canonical Wnt pathway. This pathway consists of interacting signalling molecules and induces cells to divide more quickly, thereby mediating the correct formation of the neural tube for example, which later becomes the cranial neural crest, amongst other things. As cadherin-11 can bind to and remove an important player (ß catenin) from this network, it interferes with the signalling processes. It can be expected that in so doing, cadherin-11 also interferes with the development of frog embryos.
Last but not least, Köhler and her team’s research suggests that the molecule also seems to play a role in the differentiation of precursor cells into neural crest cells. These studies will soon be published. In an ongoing project with researchers of the Heidelberg Academy of Sciences, Köhler is investigating how the protein mediates its adhesion to an artificial surface of a cell culture dish. The dish serves as model for the surface of a neighbouring cell in living tissue. The researchers hope to find out whether the cadherin molecule acts as an induction factor that is required for the tissue to develop into a functional neural crest. The researchers’ results show that only cells that are able to recognize cadherin-11 on the surface of neighbouring cells are able to form filopodial protrusions, adhere to the neighbouring cells, and thus ensure the development of the neural crest.“We are slowly unravelling what is a complicated picture,” said Köhler. Cadherins play a role in keeping tissue together; they mediate the adhesion of cells by connecting up to the cadherins of neighbouring cells. However, the cadherins can also mediate the dispersion of cells, and are therefore taking on a growing role in cancer research. Whether cadherins mediate adhesion or dispersion depends on the cell type, the cadherin type involved, its interaction partners and the quantity of the interaction partners. Köhler and her group of researchers will continue working on the completion of the differentiated picture, which, once finalized, has the potential to be used for the development of anti-cancer treatments.
Further information: Dr. Almut Köhler Karlsruhe Institute of Technology (KIT)Department of Cell and Developmental BiologyInstitute of Zoology IIFritz Haber Weg 276131 KarlsruheTel.: +49 (0)721/ 608 46380Fax: +49 (0)721/ 608 43992E-mail: almut.koehler(at)kit.edu