Nuclear Receptor Controls Nematode Metabolism And Development: Insight Into Man’s Nemesis, the Conqueror Worm
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The nuclear receptor DAF-12 plays a central role in controlling the larval development of C. elegans. Activation of DAF-12 by its ligands called dafachronic acids (DAs) commits the nematode to development into reproductive adult, which will otherwise arrest at a diapause stage called dauer. But the molecular mechanisms remain unclear. Furthermore, whether the DAF-12 signaling pathway is conserved in other nematode species, especially parasitic ones, is also unknown. One aspect of my studies is to investigate the molecular mechanisms by which this DA-DAF-12 signaling pathway regulates the C. elegans development. By measuring a series of metabolic parameters, we demonstrated that DAF-12 activation markedly elevated aerobic utilization of fatty acids. In accordance with this, expression of a network of metabolic genes responsible for energetic catabolism of fatty acids was up-regulated as well. Importantly, inhibition of these metabolic genes abolished the reproductive growth stimulated by DAF-12. These results revealed a DAF-12-controlled metabolic network that coordinates energy metabolism and larval development in C. elegans. The other emphasis of my work is on the role of DAF-12 in parasitic nematodes. Our results showed that, as seen in C. elegans, DAF-12 activation also induced recovery from the infective L3 (iL3), which is the dauer larva of the parasites. Moreover, the metabolic genes controlled by C. elegans DAF-12 were identified in parasitic nematodes. These facts indicate that the DAF-12 signaling pathway is conserved in parasitic nematodes. Importantly, administration of DA dramatically reduced the formation of the pathogenic larvae that are mostly resistant to current anthelmintic drugs, indicating the unique therapeutic potential of DAF-12 ligands to treat nematode parasitic diseases. To understand the pharmacology of targeting DAF-12, we solved the 3-demenstional structure of DAF-12 in a parasitic nematode called Stronglyloides stercoralis that infects human. These results reveal the molecular basis for DAF-12 ligand binding and identify DAF-12 and its downstream metabolic genes as unique therapeutic targets in parasitic nematodes. Based on this, we have discovered several small molecules that activate Stronglyloides stercoralis DAF-12 and these molecules may provide lead compounds for developing novel anthelmintic drugs.