A RasGRP, C. elegans RGEF-1b, Couples External Stimuli to Behavior by Activating LET-60 (Ras) in Sensory Neurons

SummaryRasGRPs, which load GTP onto Ras and Rap1, are expressed in vertebrate and invertebrate neurons. The functions, regulation, and mechanisms of action of neuronal RasGRPs are unknown. Here, we show how C. elegans RGEF-1b, a prototypical neuronal RasGRP, regulates a critical behavior. Chemotaxis to volatile odorants was disrupted in RGEF-1b-deficient (rgef-1−/−) animals and wild-type animals expressing dominant-negative RGEF-1b in AWC sensory neurons. AWC-specific expression of RGEF-1b-GFP restored chemotaxis in rgef-1−/− mutants. Signals disseminated by RGEF-1b in AWC neurons activated a LET-60 (Ras)-MPK-1 (ERK) signaling cascade. Other RGEF-1b and LET-60 effectors were dispensable for chemotaxis. A bifunctional C1 domain controlled intracellular targeting and catalytic activity of RGEF-1b and was essential for sensory signaling in vivo. Chemotaxis was unaffected when Ca2+-binding EF hands and a conserved phosphorylation site of RGEF-1b were inactivated. Diacylglycerol-activated RGEF-1b links external stimuli (odorants) to behavior (chemotaxis) by activating the LET-60-MPK-1 pathway in specific neurons.

► RGEF-1b, a neuronal Ras GTP exchange factor, is essential for chemotaxis to odorants
► DAG activates RGEF-1b in vivo; Ca2+ binding and phosphorylation are not required
► RGEF-1b couples DAG to behavior by activating a Ras-ERK cascade in sensory neurons
► A C1 domain governs targeting, catalytic activity, and in vivo function of RGEF-1b