Oxygen (O2) is a crucial molecule for the life of aerobic organisms, and all animals respond to O2 behaviorally and physiologically. For C. elegans, >2% O2 is required for normal reproductive growth. Grown under standard laboratory conditions, wild-type N2 animals prefer 8-12% O2 when tested in an O2 gradient. This preference can be suppressed by the presence of food. We are interested in understanding how C. elegans senses O2 and the neural circuit that regulates O2 preference. More specifically, we would like to identify the neurons and molecules that detect O2 and the factors that modulate preference.In previous studies, we found that the soluble guanylate cyclase GCY-35 and the cGMP-gated channel TAX-4 are required for normal O2-dependent behaviors (Gray et al., 2004). GCY-35 can bind directly to molecular O2 through a heme-binding domain, and cGMP production by GCY-35 is hypothesized to regulate the cGMP-gated channel TAX-4/TAX-2. GCY-35 is coexpressed with the soluble guanylate cyclase GCY-36 in the body sensory neurons URX, AQR, and PQR, and GCY-35 and GCY-36 cooperate to regulate social feeding (Cheung et al., 2004). Like
gcy-35 and
tax-4 mutants,
gcy-36 mutants accumulate at higher O2 concentrations than N2 in an O2 gradient. Mutants in four of the remaining five soluble guanylate cyclases (
gcy-31 to
gcy-34) are either normal or only subtly altered in O2 preference in a 0-21% gradient.Rescuing
gcy-35 and
tax-4 in URX, AQR, and PQR restores wild-type O2 preference, but URX, AQR, and PQR are not the only O2-sensing cells in C. elegans: aerotaxis is nearly normal when they are killed. We are undertaking rescue experiments to identify the other O2-sensing neurons and calcium imaging experiments to determine if they directly respond to O2. Our results suggest that O2 sensing and preference are regulated by integrated signaling in at least three classes of sensory neurons.What determines the preferred level of O2? The hypoxia inducible transcription factor HIF-1 is a highly conserved regulator of O2 responses.
hif-1 mutants have nearly normal O2 preferences, but O2 preferences are significantly shifted by mutations in
egl-9, a dioxygenase/prolyl hydroxylase that causes HIF-1 degradation.
egl-9 mutants prefer lower O2 concentrations than wild-type (5-8%). The altered O2 preference of
egl-9 mutants is suppressed by mutations in
hif-1, suggesting that increased expression of
hif-1-regulated genes changes O2 preference. EGL-9 and HIF-1 are expressed in many cells, including sensory neurons. We are taking a candidate approach to identify targets of EGL-9 in changing O2 preference and food regulation.