Talk abstracts
Talk on Friday 02:20-02:35pm submitted by Dustin Servello
Deltalike-3 acts as a co-ligand/decoy: a novel mechainsm of Notch signaling regulation
Dustin Servello (Molecular, Cellular, and Developmental Biology), Daniel Beyer (Molecular Genetics)
Abstract:
Notch signaling is a highly conserved pathway that regulates the development of many organ systems in vertebrates. Oscillatory Notch activation regulates cell differentiation of neural progenitors and intestinal stem cells as well as progression of neuroendocrine, breast, and ovarian cancers. Oscillations in the expression of Notch1, Dll1, and Lfng in mammals are required for timing the segmentation clock function that patterns mesoderm into the axial skeleton with minor disruptions in the oscillatory expression of these genes resulting in abnormal somitogenesis. A Notch ligand, DLL3, that does not have oscillatory expression and can only cis-inhibit Notch signaling is also required for normal segmentation. How DLL3 regulates the clock is largely unknown. We hypothesize that DLL3 acts as a co-ligand/decoy that promotes cells to interconvert between signal-sending and signal-receiving roles. We find that DLL3 and LFNG have distinct effects on Notch activity and that loss of Dll3 is epistatic to loss of Lfng. We show that co-expression of DLL1, DLL3, and NOTCH1 results in a loss of NOTCH1 protein likely due to NOTCH1 degradation. Additionally, co-expression of DLL3 and DLL1 in signal-sending cells results in increased Notch activation in signal-receiving cells. Our data suggests that the increased signal-sending capacity is due to DLL3 enhancing cell surface presentation of DLL1 and these processes may be altered by LFNG-dependent glycosylation of DLL3. We have also discovered an ortholog of DLL3 in the avian lineage that is modified, trafficked, and acts on the Notch signaling pathway in a similar manner showing conservation of our mechanism across evolution. We have identified a novel mechanism in regulating Notch signaling oscillations that lay the foundation for the development of many cellular lineages in the nervous, skeletal, and many other organ systems.
Keywords: DLL3, Notch signaling , avian