Solving the mechanism of Notch activation: a geneticist's perspective

Notch mediates cell fate decisions in development and tissue homeostasis and can act as an oncogene or a tumor suppressor depending on the cell context. In my first essay for the GENETICS Perspectives series, "Notch and the Awesome Power of Genetics," I gave my perspective on developments in the field in the 20th century, from the isolation of the eponymous Notch mutations in Drosophila through the elucidation of the mechanism of signal transduction. That essay had a bildungsroman quality about it because the burgeoning of the Notch field and the increasing impact of Caenorhabditis elegans as a model organism coincided with my development as a scientist. But the "awesome power of genetics" was the guiding star of the essay because genetic approaches were largely responsible for identifying the core components of the signaling system and for deducing the novel cleavage mechanism by which Notch transduces signals. In this sequel, I offer my perspective as a geneticist on how the awesome power of genetics continued to have a starring role in the mechanistic discoveries that followed during the first quarter of the 21st century. I aim to show how genetics remains essential both in posing questions and in answering them even as the molecular events associated with activation of Notch signal transduction continue to be elucidated in exquisite structural detail.