Dr Martin Zeidler

Martin Zeidler was an undergraduate at the University of Sussex before moving to the European Molecular Biology Laboratories (EMBL) in Heidelberg to undertake his DPhil studies in the laboratory of Dr Marek Mlodzik. In 1996 he moved to Harvard Medical School in Boston, USA to undertake postdoctoral studies in the laboratory of Professor Norbert Perrimon where he begun studying the Drosophila JAK/STAT signal transduction pathway. In 2001 he was awarded a prestigious Emmy Noether award of the Deutsche Forschungs Geselschaft (DFG) to establish his own laboratory at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany. During this time his lab continued to study the JAK/STAT pathway and established himself as a leading member within the field. In 2006 the Zeidler lab relocated to the department of Biomedical Science at the University of Sheffield before joining the Centre for Developmental & Biomedical Genetics. Dr. Zeidler was promoted to Reader and awarded a Cancer Research-UK Senior Cancer Research Fellowship in 2007.

Research

Summary for nonspecialist

The blood cells required to transport oxygen around our body and protect us from infection have a limited life span and must be regularly replaced. These replacements are made within the bone marrow where stem cells continuously divide and are instructed to specialise to the various red and white blood cell types required.

The information and instructions that control this process of stem cell proliferation and maturation is supplied by a number of signals whose effects are transmitted by the JAK/STAT signalling cascade (amongst others). While absolutely required for normal blood cell development, mutations that cause inappropriate activation of the JAK/STAT pathway are potentially dangerous and can lead to the uncontrolled cellular proliferation and a range of leukaemias, lymphomas and meyoproliferative diseases.

The Zeidler lab is interested in identifying and understanding how the regulators of JAK/STAT signalling work and how they may be involved in development and haematopoiesis with the ultimate aim of using this understanding to be able to better treat human blood cell malignancies.

Technical summary

What is JAK/STAT signalling?

Signal transduction cascades consist of interacting molecules that react to an external stimulus by producing an appropriate, timely and controlled cellular response. The transfer of information between cells facilitated by signalling pathways is essential for the development and survival of all multi cellular organisms and is undertaken by a relatively small number of distinct pathways pathways.

The JAK/STAT pathway is one of these signalling cascades and was first identified in the early 1990s as a cellular response to interferon. Since this initial identification, a broad international research effort has characterised the core pathway components and their interactions with one another (Figure 1).

Components of the JAK/STAT pathway have been conserved throughout evolutionary time and an intact signalling pathway, similar to that in humans, is also present in the fruitfly Drosophila melanogaster. Although the Drosophila pathway is considerably less complex than its equivalent in mammals, many of the roles played by the pathway are common to both systems. For example, blood development, cellular proliferation and immune responses all require JAK/STAT signalling in both organisms.

This fundamental conservation is also reflected at the level of human disease. For example, a number of myoproliferative blood cell cancers have recently been shown to result from an activating mutation in human JAK1. Strikingly similar effects also occur in flys where an activating mutation in Drosophila JAK (termed hop^Tuml) leads to a massive increase in the number of blood cells and the formation of melanotic tumours (Figure 2). Using straightforward Drosophila genetic techniques, experiments can then be undertaken to assay in vivo disease progression - a process that can be significantly reduced by mutations in other pathway components (Figure 2).

How do we study the pathway?

My laboratory uses both genetic and cell based assays to identify loci that interact with the JAK/STAT signalling pathway. In collaboration with the Boutros group at the DKFZ (Heidelberg, Germany) we have used a whole-genome RNAi approach to systematically knock down every transcript within the Drosophila genome. Using this technique we have identified over 90 known and previously unknown loci which function to regulate the pathway.

Ongoing efforts in the laboratory are focused on the further analysis of JAK/STAT pathway regulating genes to determine the molecular basis of their interaction with the pathway. By using the advantages of the Drosophila system while validating our findings in more complex human cell based models we hope to be able to gain a deeper understanding of the regulators whose disfunction may lie at the heart of human disease.