Iva S. Greenwald
LIN-12/Notch proteins are receptors that mediate cell-cell interactions during animal development. Ligand binding triggers proteolytic cleavages in the extracellular and transmembrane domains; the intracellular domain translocates to the nucleus and forms a complex with a sequence-specific DNA binding protein, converting it from a repressor to an activator of target gene transcription.Mutation of core components and modulators of the LIN-12/Notch pathway have been associated with major human diseases, including cancer and Alzheimer's disease.We have identified many such genes through conventional mutagenesis and RNAi-based genetic screens. They are of interest as potential therapeutic targets as well as for the potential insight they offer into fundamental mechanisms underlying animal development.
We study two paradigms in which cell-cell interactions mediated by LIN-12/Notch cause equivalent cells to adopt distinct cell fates. These paradigms allow us to deduce fundamental logic and describe molecular events underlying cell fate decision-making. One is a simple lateral specification paradigm, the anchor cell (AC)/ventral uterine precursor cell (VU) decision. During the AC/VU decision, two initially equivalent cells interact with each other, activating feedback mechanisms that cause bidirectional signaling to become unidirectional.In the other paradigm, Vulval Precursor Cell (VPC) patterning, LIN-12/Notch signaling is integrated with other signaling inputs. The fundamental question is how these different signaling events are coordinated. We have identified modes of cross-talk with the EGFR-Ras-MAPK pathway, andhave also investigated other putative signaling inputs, to get a more comprehensive view of the signaling events with which LIN-12/Notch signaling is coordinated. Some of our work has challenged prevailing views about these events. We have also begun to investigate how developmental timing mechanisms impact on LIN-12/Notch signal transduction.