, 2007 and Toki et al., 2001). However, functions, regulation, and effectors of neuronal RasGRPs are unknown. We have elucidated regulatory properties, a physiological function and effectors of RGEF-1b, a RasGRP homolog, in C. elegans sensory neurons. RGEF-1b has conserved catalytic, EF-hand, and C1 domains JAK inhibitor that are hallmark features of RasGRPs. PMA and DAG recruit RGEF-1b

from cytoplasm to membranes and stimulate its catalytic activity. Both LET-60 and RAP-1 are RGEF-1b substrates. Thus, RGEF-1b is a new, but prototypical RasGRP. The rgef-1 gene promoter is active in neurons. Transcription was initiated just prior to hatching of L1 larvae. Promoter activity was sustained in all larval stages and adulthood. After hatching, C. elegans relies on extrinsic stimuli (food, ions, etc.) to guide its behavior. The neuron-specific and temporal

patterns of rgef-1 gene expression suggest RGEF-1b could mediate behavioral responses to environmental stimuli throughout postembryonic life. Chemotaxis to volatile odorants was impaired in RGEF-1b-deficient animals. Panneuronal or AWC-selective expression of RGEF-1b-GFP restored chemotaxis in rgef-1−/− animals. Conversely, GDC-0199 in vivo panneuronal or AWC-selective expression of dominant-negative RGEF-1bR290A-GFP disrupted odorant-induced chemotaxis in WT animals. Thus, RGEF-1b is indispensable for a fundamentally important C. elegans behavior. Odorant-induced chemotaxis enables acquisition of nutrients that optimize health and reproduction. The discovery that RGEF-1b mediates chemotaxis

establishes a neuronal function for a click here RasGRP. The insight that expression of RGEF-1b in AWC neurons restores chemotaxis to attractive odorants illuminates the cellular basis for the rgef-1−/− phenotype. Signals disseminated by a DAG-activated RasGRP in AWC sensory neurons are essential for complex behavior of an intact animal. RGEF-1b loads GTP onto LET-60 and RAP-1. Expression of constitutively active LET-60G12V in AWC neurons restored chemotaxis to odorants in RGEF-1b-deficient animals. Accumulation of dominant-negative LET-60S17N in AWC neurons (WT background) inhibited chemotaxis. Neither constitutively active nor dominant-negative RAP-1 affected chemotaxis. Thus, RGEF-1b couples odorant stimuli to chemotaxis via LET-60-GTP. The AGE-1-AKT-1 and LIN-45-MEK-2-MPK-1 signaling modules are effectors of LET-60-GTP (Han et al., 1993 and Nanji et al., 2005). Elimination of AGE-1 activity from a temperature sensitive mutant and characterization of nematodes carrying a hypomorphic allele of age-1 revealed that PI3K deficiency enhanced chemotaxis to BZ and BU. Thus, the LET-60-AGE-1-AKT-1 pathway is not required for attraction to odorants. Expression of constitutively active MEK-2-GFP(gf) restored AWC-dependent chemotaxis in the rgef-1−/− background.