Research Team - Prof. Dr. A. Preiss

Negative regulation of Notch signal transduction in Drosophila melanogaster

Development of multicellular organisms requires cells to adopt different paths. In Eumetazoan, tis process is regulated by the Notch signalling pathway. Activation of the Notch receptor by one of its ligands presented on the surface of a neighbouring cell results in receptor cleavage. The intracellular domain of the Notch receptor ICN migrates to the nucleus to assemble an activator complex on Notch target gene promoters. This activator complex comprises the DNA-binding protein Su(H) and several co-activators like Mam, resulting in the transcriptional activation of Notch target genes.

In the absence of signals Notch target genes are silenced by a repressor complex consisting of Su(H) and several co-repressors. In Drosophila the major antagonist of Notch is encoded by Hairless (H), which binds to Su(H) as well as two general co-repressors Groucho and CtBP (1). Accordingly, Su(H) acts a molecular switch either activating or repressing Notch-target genes. Currently, we are investigating the mechanisms underlying the switch (2,3), as well as the cross-talk to other signalling pathways (4).

Hairless is a rather large protein consisting of several functional domains including the binding sites for Su(H), Groucho and CtBP. In addition we have identified several binding partners of Hairless including Pros26.4 and CycG. Pros26.4 belongs to the regulatory subunits of the 26S proteasome in Drosophila. It is involved in the specific degradation of Hairless, hence positively influencing Notch signalling activity (5). A further partner of Hairless is Drosophila Cyclin G protein (6). Whereas mammalian CycG is activated in response to p53, Drosophila CycG is important for DNA double strand break repair during meiosis (7). Moreover, it is an important positive regulator of InR/Tor signalling activity (8).

Ausgewählte Publikationen:

1. Nagel, A.C., Krejci, A.,Tenin, G., Bravo-Patiño, A., Bray, S., Maier, D. and Preiss, A. (2005). Hairless mediated repression of Notch target genes requires co-operation between Groucho and CtBP co-repressors. Mol. Cell Biol. 25 (23), 10433-10441. Mol Biol Cell 21, 3443-344.
2. Nagel, A.C., and Preiss, A. (2011). Fine tuning of Notch signaling by differential co-repressor recruitment during eye development of Drosophila. Hereditas 148, 77-84.
3. Maier D., Kurth P., Schulz A., Russell A., Yuan Z., Gruber K., Kovall R.A., Preiss A. (2011). Structural and functional analysis of the repressor complex in the Notch signalling pathway of D. melanogaster. Mol Biol Cell 21, 3242-325.
4. Auer J.S., Nagel A.C., Schulz A., Wahl V., Preiss A. (2015) MAPK-dependent phosphorylation modulates the activity of Su(H) in Drosophila. Cell. Signal. 27, 115-12.
5. Müller, D., Nagel, A.C., Maier, D. and Preiss, A. (2006). Molecular link between Hairless and Pros26.4, a member of the AAA-ATPase subunit of the proteasome 19S regulatory cap in Drosophila J. Cell Sci. 119,  250-2587.
6. Nagel A.C., Szawinski J., Zimmermann M., Preiss A. (2016). Drosophila Cycling G is a regulator of the Notch signalling pathway during wing development. PloS One 11(3): e0151477. 
7. Nagel, A.C., Fischer, P., Szawinski, J., La Rosa, M.K., Preiss, A.(2012). Cyclin G is involved in meiotic recombination repair in Drosophila melanogaster. J Cell Sci 125, 5555-5563
8. Fischer P., La Rosa M.K., Schulz A., Preiss A., Nagel A.C.(2015). Cyclin G functions as a positive regulator of growth and metabolism in Drosophila. PLOS Genetics 11(8):e1005440