The Notch signaling pathway is one of the few highly conserved cell signaling mechanisms that guide cell fate decisions during development and maintenance of multicellular organisms. Notch signals exhibit remarkable pleiotropy depending on the specific biological context controlling processes such as cell proliferation, differentiation, apoptosis, and migration. Dysfunctions in Notch signaling are often linked to various diseases, including multiple types of human cancers.
Signaling initiation requires direct cell-cell contact, whereby ligand-receptor binding triggers receptor cleavage and the subsequent release of its intracellular domain (NICD). NICD in turn is a transcriptional regulator that translocates into the nucleus and directly influences the expression of Notch target genes.
Our research focus is to understand the spatiotemporal dynamics of Notch signaling, how it is regulated and how it in turn dictates signaling output in various biological contexts.
In our recent work, we applied advanced microscopy techniques to visualize the endogenous events of Notch signaling transduction in living cells (Tveriakhina, Scanavachi et al., 2024). We observed that ligands and receptors formed synapses with a stoichiometry of 1:1 seconds after the cells met. Synapses were short lived and dissolved 15-20 minutes after giving rise to nuclear NICD. We further quantified the number of molecules involved in signaling transduction.
Currently, we are elucidating the properties and dynamics of cell membranes and endocytic events and how they impact signaling initiation and transduction. We use single cell and human induced pluripotent stem cell (hiPSC)-derived organoid model systems to observe and compare endogenous signaling events in various contexts. We utilize gene editing, live cell-cell co-cultures and reconstitution techniques and combine multidisciplinary approaches such as advanced quantitative live-cell imaging, EM, proteomics, and transcriptomics to gain a comprehensive understanding of the pleiotropy of Notch signaling at cellular and molecular level.
Tveriakhina Lab 