C. elegans detects several odorants with the bilaterally symmetric pair of AWC olfactory neurons. A stochastic, coordinated decision ensures that the candidate odorant receptor gene str-2 is expressed in only one AWC neuron in each animal--either the left or the right neuron, but never both. An interaction between the two AWC neurons generates asymmetric str-2 expression in a process that requires normal axon guidance and probably AWC axon contact. This interaction induces str-2 expression by reducing calcium signaling through a voltage-dependent Ca2+ channel and the CaM kinase II UNC-43. CaMKII activity acts as a switch in the initial decision to express str-2; thus, calcium signals can define distinct cell types during neuronal development. A cGMP signaling pathway that is used in olfaction maintains str-2 expression after the initial decision has been made.

The Gi/Go-like G alpha protein ODR-3 is strongly and selectively implicated in the function of C. elegans olfactory and nociceptive neurons. Either loss of odr-3 function or overexpression of odr-3 causes severe olfactory defects, and odr-3 function is essential in the ASH neurons that sense noxious chemical and mechanical stimuli. In the nociceptive neurons, ODR-3 may interact with OSM-9, a channel similar to the mammalian capsaicin receptor implicated in pain sensation; in AWC olfactory neurons, ODR-3 may interact with another signal transduction pathway. ODR-3 exhibits an unexpected ability to regulate morphogenesis of the olfactory cilia. In odr-3 null mutants, the fan-like AWC cilia take on a filamentous morphology like normal AWA cilia, whereas ODR-3 overexpression in AWA transforms its filamentous cilia into a fan-like morphology.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein WldS prevent this rise. These data indicate that the mechanism by which NMNAT and the related WldS protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.