Background: Notch proteins are master regulators of cell fate during development and control selfrenewal and differentiation in most adult tissues. Activation of Notch proteins is regulated by successive enzymatic cleavages that release the cell membrane-bound form that acts as a transcriptional regulator. Notch activity is also regulated by intracellular trafficking but how localization and activity are connected is unclear. We recently identified metal-binding transporters as novel key mediators of intracellular Notch trafficking and activity.
Key objectives: 1) To identify the importance of metal transport(er), vesicular trafficking and Notch activity and 2) to interfere with metal transport to block Notch activity in tumours or promote regeneration of normal cell types. You will apply gain and loss of function (CRISPR, siRNA, pharmacological) in Notch-dependent 2D and 3D models (cell lines, normal and tumour organoids (lung, intestine) and high-resolution fluorescent imaging (confocal, STED) and single-cell tissue analysis to decipher how metal transport influences Notch signaling to direct cell specification and cell renewal.
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