Ras Effector Switching Promotes Divergent Cell Fates in C. elegans Vulval Patterning

The C. elegans vulva is patterned by epidermal growth factor (EGF) activation of Ras to control 1 degrees fate, and 1 degrees fate induces antagonistic Notch-dependent 2 degrees fate. Furthermore, a spatial EGF gradient, in addition to inducing 1 degrees fate, directly contributes to 2 degrees fate via an unknown pathway. We find that in addition to its canonical effector, Raf, vulva! Ras utilizes an exchange factor for the Ral small GTPase (RalGEF), such that Ras-RalGEF-Ral antagonizes Ras-Raf pro-1 degrees fate activity. Consistent with its restricted expression pattern, Ral participates in EGF pro-2 degrees activity. Thus, we have delineated a Ras effector-switching mechanism whereby position within the morphogen gradient dictates that Ras effector usage is switched to RalGEF from Raf to promote 2 degrees instead of 1 degrees fate. Our observations define the utility of Ras effector switching during normal development and may provide a possible mechanistic basis for cell and cancer-type differences in effector dependency and activation.