Thomas Klein has received his Ph.D. in Cologne 1994, where he worked on the function of the Drosophila gene klumpfuss during adult neurogenesis. He then joined the lab of William Chia at the University of Singapore for 14 month before moving on to the lab of Alfonso Martinez-Arias at the University of Cambridge, UK.

In 1999 he moved to the University of Cologne as an independent group leader. His work covers several aspects of adult development of the fruit fly Drosophila melanogaster, in which the Notch-signalling pathway plays a role, such as wing, leg and head development as well as neurogenesis.

- Thomas Klein is Professor at the Institute of Genetics in Düsseldorf since 2007. -

Past research:

The main focus throughout my career has been in the use of Drosophila melanogaster as a technological platform to study cellular and molecular aspects of development. Within this experimental framework my group has been studying two processes in parallel.

The first one is the generation of large-scale pattern in a growing tissue and uses the developing wing as experimental ground.

The second is the specification and patterning of neural precursors in the peripheral nervous system of the adult.

Our studies have uncovered the activity of the Notch receptor as a central element in both processes and has demanded an intense focus on the regulation of Notch signalling. By studying the regulation of one of the central genes in wing development, vestigial (vg), we were able to show that the wing is an outgrowth of the body wall and that Vg provides the molecular context in which the more general signals produced by the major signalling pathways Notch, Hedgehog and Wg/Wnt are interpreted in a wing-like manner. Furthermore, we could show that the major transcriptional mediator of the Notch signal, Suppressor of Hairless (Su(H)), acts as an activator as well as an suppressor of transcription. In the absence of its function, a subgroup of Notch target genes is de-repressed. The de-repression is the explanation for the puzzling observation that the phenotype of Su(H) mutants is weaker than that of other genes involved in Notch signalling. Because of the weakness of the Su(H)-mutant phenotype in several developmental processes alternative, Su(H)-independent pathways of Notch-signalling have been suggested in the past. The results show that these pathways do not exist during wing and bristle development and that the phenotype of Su(H) mutants can be explained by its dual function.

The results further led to a new understanding of the molecular mechanism operating during the formation of the dorso-ventral compartment boundary (D/V-boundary), where Notch plays a crucial role. They show that, in contrary to what has been published before, Su(H) is involved in this process and that the strategy used to establish the D/V-boundary is similar to that operating during formation of the antero-posterior compartment boundary.

We have recently started to investigate the function of the transcription factor defective proventriculus (dve) during wing development. The loss of this factor results in a deletion of a part of the proximo-distal axis. The characterisation of the function and regulation of dve uncovered a novel mechanism that patterns a part of this axis of the wing. Currently, we are investigating this mechanism in detail. During the development of the Imago, the Notch pathway is involved in the selection of the neural precursor cells (SOP´s) among cells of equivalence groups, called proneural clusters. We could specify the role of Notch within this process. We provided evidence that Notch is not required for the selection of the SOP (as so far assumed), but to prevent all cells in the cluster except the future SOP to adopt the SOP fate. Our work revealed that an unidentified process of unexpected preciseness operates in the cluster to select the SOP and render the future SOP insensitive to the Notch signal. Furthermore, the study of the function of Su(H) during this process indicates that this transcription factor has also Notch-independent functions in this process.

More recently, we have begun to use the mouse as a system to test the generality of the mechanisms that we uncover in Drosophila.

Main projects of the lab

At the moment my lab has two major research focuses, which will be also the main projects in the foreseeable future. One project is the characterisation of the tumour suppressor gene lethal(2)giant discs (lgd). We have shown that this gene is a general regulator of the activity of the Notch signalling pathway in Drosophila and possibly in vertebrates. This pathway is found in all multi-cellular animals and is involved in a multitude of developmental processes as well as for stem cell maintenance in many tissues in vertebrates. Furthermore, Notch plays a role in cancer and inherited diseases. If the function of lgd is lost, Notch is active in all imaginal disc cells in a ligand-independent manner. This is the first in vivo demonstration of a ligand-independent activation of the Notch receptor. Our results show that Lgd is probably involved a constitutive, ligand-independent turnover of the non-activated Notch receptor: If the function of lgd is lost, Notch accumulates in a late endosomal compartment and is spontaneously activated by an unknown mechanism. We found that lgd encodes a member of a novel protein family that conserved throughout the animal kingdom. The function of these proteins is not understood.

We are currently focus our efforts to determine the precise function of Lgd during endosomal trafficking of Notch. Furthermore, we have started to generate conditional KO alleles of the murine orthologs of Lgd, mLgd1 and mLgd2. We will use these alleles to study the function of Lgd during mouse development and in tissue homeostasis.