Laboratory of Developmental Biology
Head of the laboratory: Alena Krejci
Communication between cells is crucial during embryonic development as well as in every aspect of the adult life of a multicellular organism. Cells use various signalling pathways to detect changes in their environment and respond to them appropriately, for example by changing their transcription, activity of various proteins or by adjusting their metabolism. There are relatively few signalling pathways, conserved throughout the multicellular. However, cell's response to the activity of these pathways can differ profoundly, depending on cellular context. Various factors influence the final output of signalling pathways, such as the expression of proteins enhancing or silencing the signalling relay, the strength and duration of the signal, or transcription factors present in a given cell type. One of the recently emerging factors that can significantly affect cell signalling is the concentration of various metabolic intermediates, in other words the type of cellular metabolism.
Specific modes of metabolism seems to be crucial for individual cell types and their disruption can have profound consequences for cell function and fate. Metabolism is no more considered as a passive provider of cellular energy and building blocks for the cell but it is one of the key factors regulating cell survival, proliferation, transcription, chromatin or signalling. For example, metabolic switch towards high glycolysis uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation, known as the Warburg effect, is typical for proliferating cells, immune cells, stem cells and cancer cells. Interestingly, there is emerging evidence that alternation of metabolism might sometimes be the cause, rather than a consequence, of cancerous growth.
Metabolic sensors are proteins whose activity is sensitive to changes in the concentration of specific cellular metabolites. These proteins include transcription factors, structural proteins or enzymes and they therefore connect cellular metabolism with other cellular processes. For example, sirtuins are proteins that deacetylate certain cellular targets and whose activity is strictly dependent on the availability of NAD+. Therefore, in conditions of metabolic stress when the concentration of NAD+ is rising, sirtuins become more active and this can have profound consequences on the cell's behaviour. Recent research identified hundreds of such proteins that are able to bind various metabolic intermediates and that can therefore serve as metabolic sensors.
In our laboratory we are interested in the interplay between cell signalling and metabolism, using Drosophila as a model organism.
1. The Notch signalling pathway and its interplay with cellular metabolism.
Signalling via Notch receptor is one of the most important and well conserved signaling pathways that controls many different cellular decisions and is associated with several diseases, including cancers. We showed that this pathway regulates several metabolic genes and this way it mediates metabolic shift in the target cells towards the Warburg effect (Slaninova V, 2016) . On the other hand, we showed that Notch pathway is sensitive to perturbations in the cellular metabolic status through the crosstalk with Sirtuin 1 protein metabolic sensor (Horvath, 2016).
2. Signalling pathways triggered by mitochondrial dysfunction
Mitochondria play an essential function in cellular energetic and NADH metabolism. Through an RNAi based screen in Drosophila wings we identified NADH-binding subunits of respiratory complex I as mediators of major signalling changes during wing and eye discs development. We decipher the signalling network associated with respiratory dysfunction that involves the interplay between the TOR, JNK, JAK/STAT and Notch pathways. As mitochondrial respiratory disorders are one of the most common human genetic diseases and mitochodrial metabolism is often disturbed in cancer, the detailed signalling network we describe is relevant for understanding of mechanisms behind these pathologies.
3. The crosstalk between metabolism and imunity
Immune cells require large amounts of nutriets to proliferate and to fight pathogens. We identified a new gene expressed in immune cells and in the fat body that regulates proliferation of immune cell progenitors and the metabolic adaptations during infection. We are characterizing the mechanism of action of this gene to mediate the crosstalk between immunity and metabolism.