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Developmental signalling pathway: from its essentials to applied biosensors Working with zebrafish has opened a wide range of possibilities to explore the relations between transcription factors and cell fate decisions. In the last years we have indeed explored this field taking advantage of transgenic technologies and now we lead a new approach in the characterization of signalling pathways involved in organ and tissue development and homeostasis. Our approach is using artificial ultra-enhancers built by polymerization of transcription factor responsive elements. These ultra-enhancers can be used to reveal in vivo, at single cell resolution, regions of activities for the main genetic pathways controlling proliferation and/or differentiation. With this approach we have been able to prepare a collection of living biosensors that are currently used world wide for the phenotyping of mutants and tumours, drug screening, characterization of gene functions both in normal development and models of disease. We think this approach is the dawn of a new era of quantitative biology able to exploit zebrafish transparency and genetic manipulability (CRISPR/Cas) together with linearity and sensitivity of ratiometric fluorescent signals, for the production of miniaturized models of disease at single cell resolution.

STAT3 is a gene encoding a nuclear transcription factor controlling stemness, NR3C1 is the gene encoding the Glucocorticoid receptor, a nuclear transcription factor (glucocorticoid is a widely used class of drugs) and Hif1a is the nuclear transcription factor that is responsible for hypoxia response. Data from literature indicate that this three transcription factors have strong interactions in controlling respiration, metabolism and proliferation. Our laboratory is aimed at: 1) Define the Gene Regulatory Network of STAT3, NR3C1and HIF1a in simple model systems 2) Define the molecular mechanisms coordinating nuclear and mitochondrial expression by STAT3, NR3C1 and HIF1a in simple model systems 3) Define the impact of Hif1a, NR3C1, STAT3 mutations on mitochondria biology 4) Target the mitochondrial functions of STAT3, NR3C1 and HIF1a in regenerating tissues and small cancer models