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Archaic flare reveals the mechanisms of cell differentiation

There are only a few signalling pathways that have been as well conserved during evolution as the Notch signalling pathway. This is due to the pathway’s unique biological function. Notch enables two identical cells to develop into completely different tissues. Anette Preiß, professor at the University of Hohenheim, has been working on the function of the Notch signalling pathway for almost 20 years.

The human body needs approximately 200 different cell types to function; the cells form blood vessels, muscle tissue or highly complex organ systems. The organisational capacity is enormous given that all body cells originate from a single, fertilised egg cell. But how do newly formed cells learn their future role? The answer lies in the large number of finely adjusted signalling pathways used by the cells to communicate with each other. The Notch signalling pathway is of enormous importance for cell-cell communication. The first Notch receptor mutations were described as far back as almost 100 years ago.
Prof. Dr. Anette Preiß from the University of Hohenheim is investigating the mechanisms of the Notch signalling pathway. (Photo: BioRegio STERN)
“The Notch signalling pathway is used to create two different cells from two identical ones,” said Professor Anette Preiβ from the Institute of Genetics at Hohenheim University. “However, Notch does not tell the cells what they have to do,” said the biologist explaining that Notch allows the cells to differentiate into a cell that is different from its neighbours. This concept has barely changed during the whole evolutionary process. The Notch signalling pathway is a highly conserved signalling system and is found in threadworms, fruit flies and humans. The high level of conservation is a typical sign of all signalling pathways that are of huge biological importance. “It is believed that these signalling pathways developed millions of years ago and have proved to be eminently practical,” said Preiβ pointing out that any small change in this system would have been fatal for the cells, and hence for the entire organism.

Special role of the Notch signalling pathway

This is why the principle composition of the Notch signalling pathway has remained similar in all organisms. Fruit flies (Drosophila melanogaster) have a Notch receptor and two ligands that function as the key for activating the signalling pathway. Humans have four Notch receptors and two classes of ligands, which are, however, closely related structurally to those of Drosophila. “The Notch signalling pathway is so special because both the receptor and the ligands are anchored in the cell membrane,” said Preiβ. The Notch receptor of a cell can therefore only be activated by the immediate cell neighbours. “This is unusual, because in the majority of signalling pathways the ligands, for example hormones, are produced remotely and transported to their destination in the blood,” said Preiβ.
schematic diagram of the interaction of Notch and Hairless.
In Drosophila, Notch and Hairless compete for the same target genes. (Figure: Preiß / University of Hohenheim) © Preiß / University of Hohenheim
The Notch signalling way is also special in terms of the effect it has. While the majority of known transduction pathways need to activate numerous enzyme cascades before the signal reaches the target genes, Notch chooses a far more direct path: ligand proteins that bind to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which then enters the cell nucleus to alter gene expression. “Notch is rather like a flare,” said Preiβ, “the signal is fired off immediately after contact is made with the ligands of a neighbouring cell, it lights up briefly, and then fades away.” This tracer can neither be halted nor influenced by other factors.

The mystery of the one-shot principle

“One of the greatest enigmas in biology is the function of Notch’s one-shot principle,” said Preiβ who has been working on this mystery for over 20 years. Preiβ however no longer focuses exclusively on Notch, concentrating more on its intracellular antagonist, Hairless. “I have been fascinated by Hairless for a long time because it switches off the very genes that Notch is trying to switch on,” said Preiβ who first became interested in the Notch signalling pathway during her postdoctoral period at Yale University. The unusual names of the two signalling proteins originate from two Drosophila strains; the Hairless strain has a mutation in the Hairless gene and has hardly any bristles on its surface; flies of the Notch strain have notches in their wing blades.
Photo of a mutated wingblade of Drosophila. The mutation leads to the typical notch in the wingblade, visible on the left, where the black borderline is disrupted.
Notch receptor mutations lead to typical notches in the wingblades of Drosophila. (Photo: Preiβ/University of Hohenheim)

Professor Preiβ’s group is currently investigating how Notch and Hairless compete with each other on a molecular level. “If we succeed in understanding how this works in Drosophila, then we might also gain deeper insights into human pathways, and potentially develop suitable drugs that will be able to interfere with these pathways,” said Preiβ. Disorders in the Notch signalling pathway can lead to diseases in humans. For example, the autosomal dominant disorder CADASIL, which is characterised by recurrent strokes, is caused by mutations of the Notch3 receptor. The Alagille syndrome, which is characterised by chronic liver disease, is caused by mutations of one of the ligands involved in the Notch pathway. Notch also plays a part in the development of numerous cancers. The researchers therefore have their work cut out for the future. Professor Preiβ knows from her own experience that the “Notch signalling pathway plays a role in almost all processes; it will therefore always crop up in our investigations.”

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