C. elegans Nuclear Hormone Receptor NHR-49 promotes attractive chemotaxis independently of its role in fatty acid metabolism

All organisms must sense and adapt to environmental cues to survive and thrive. In the nematode worm Caenorhabditis elegans , the nuclear hormone receptor nhr-49 is required for lipid homeostasis, stress resilience, pathogen defense, and longevity. In addition, recent studies suggest that NHR-49 controls avoidance behaviors and aversive memory to pathogenic bacteria and mitochondrial disruption, acting via its established role in fatty acid desaturation and fatty acid oxidation, respectively. However, the role of NHR-49 in neuronal signaling and behavior remains poorly understood. Here, we uncover a new role for NHR-49 in AWA neuron-mediated attractive chemotaxis. We show that nhr-49 is required for chemotaxis towards diacetyl and pyrazine, two AWA neuron-sensed compounds, but not for AWC-or ASH-mediated chemotaxis. Supplementation with unsaturated fatty acids and mutational analysis of additional genes involved in fatty acid desaturation orβ-oxidation reveal that these processes do not affect attractive chemotaxis; this suggests that NHR-49 mediates attractive chemotaxis independently of its role in fatty acid desaturation and oxidation. Tissue-specific expression of NHR-49 in neurons or body wall muscle is sufficient to rescue chemotaxis defects, while nhr-49 depletion in neurons alone causes chemotaxis defects. Finally, nhr-49 mutants also show defects in another behavior, the response and habituation to mechanosensory stimuli. Together, our data reveal new functions for NHR-49 in sensory responses and non-associative learning, which are distinct from its roles in aversive behaviors and memory and, notably, independent of its well-established role in lipid metabolism.