, 2008). With Selleck NVP-AUY922 central roles in many human biological processes, HIF PHDs are promising therapeutic targets for treating ischemic stroke, neurodegenerative diseases, and cancer (Mazzone et al., 2009 and Quaegebeur and Carmeliet, 2010). The first O2-sensing PHD enzyme identified was the C. elegans

EGL-9 protein, the product of a gene defined by mutations that cause an egg-laying behavioral defect ( Darby et al., 1999, Epstein et al., 2001 and Trent et al., 1983). C. elegans exhibits diverse genetically tractable behaviors that are regulated by internal physiological states, environmental cues, and behavioral experiences ( de Bono and Maricq, 2005, Jorgensen and Rankin, 1997 and Sawin et al., 2000). Studies of several C. elegans behaviors have significantly increased our understanding of the molecular and neural mechanisms underlying behavioral plasticity, a major problem in neurobiology. C. elegans naturally lives in soil or in microbe-rich habitats where O2 is usually reduced from the ambient level of 21% ( Félix and Braendle, 2010) and prefers hypoxic ranges of O2 concentration when tested in laboratory aerotaxis experiments ( Gray et al., 2004). Prior experience of hypoxia can activate HIF-1 and shift the animal’s O2 preference toward lower

O2 levels ( Chang and Bargmann, 2008 and Cheung et al., 2005). Hypoxia also enhances check details NaCl chemotaxis through HIF-1-dependent upregulation of TPH-1, a biosynthetic enzyme for the neural modulator serotonin ( Pocock and Hobert, 2010). While the EGL-9

pathway chronically monitors O2 changes to elicit behavioral plasticity through transcriptional regulation, acute sensing of O2 at levels ranging from 4%–21% is mediated by soluble guanylate cyclase (GCY) family proteins ( Cheung et al., 2004, Gray not et al., 2004, McGrath et al., 2009 and Zimmer et al., 2009). The evolutionarily conserved EGL-9/HIF-1 pathway is highly regulated to dynamically control the expression of many genes important for hypoxic adaptation (Powell-Coffman, 2010). As 2-oxoglutarate-dependent dioxygenases with Fe2+ and ascorbate as cofactors, HIF PHDs are sensitive to ambient O2 levels as well as to fluctuations in cell metabolic and redox status (Rose et al., 2011). In C. elegans, EGL-9 destabilizes HIF-1 via its hydroxylation and subsequent degradation by the VHL-1 complex and also inhibits HIF-1 transcriptional activity through unidentified hydroxylation-independent mechanisms ( Shao et al., 2009). Similar dual-mode inhibition of HIF has been observed for mammalian HIF PHDs ( Ozer et al., 2005 and To and Huang, 2005). In addition, the C. elegans protein RHY-1 inhibits HIF-1 independently of VHL-1 ( Shen et al., 2006), although the relationship between RHY-1 and EGL-9 and the mechanism by which RHY-1 inhibits HIF-1 remain to be established.