Abstract
Nuclear receptors of the Hepatocyte Nuclear Factor-4 (HNF4) subtype have been linked to a host of developmental and metabolic functions in animals ranging from worms to humans; however, the full spectrum of physiological activities carried out by this nuclear receptor subfamily is far from established. We have found that the Caenorhabditis elegans nuclear receptor NHR-31, a homolog of mammalian HNF4 receptors, is required for controlling the growth and function of the nematode excretory cell, a multi-branched tubular cell that acts as the C. elegans renal system. Larval specific RNAi knockdown of nhr-31 led to significant structural abnormalities along the length of the excretory cell canal, including numerous regions of uncontrolled growth at sites near to and distant from the cell nucleus. nhr-31 RNAi animals were sensitive to acute challenge with ionic stress, implying that the osmoregulatory function of the excretory cell was also compromised. Gene expression profiling revealed a surprisingly specific role for nhr-31 in the control of multiple genes that encode subunits of the vacuolar ATPase (vATPase). RNAi of these vATPase genes resulted in excretory cell defects similar to those observed in nhr-31 RNAi animals, demonstrating that the influence of nhr-31 on excretory cell growth is mediated, at least in part, through coordinate regulation of the vATPase. Sequence analysis revealed a stunning enrichment of HNF4α type binding sites in the promoters of both C. elegans and mouse vATPase genes, arguing that coordinate regulation of the vATPase by HNF4 receptors is likely to be conserved in mammals. Our study establishes a new pathway for regulation of excretory cell growth and reveals a novel role for HNF4-type nuclear receptors in the development and function of a renal system.
Highlights
Nuclear receptors (NRs) comprise a large family of transcription factors distinguished by a highly conserved DNA binding domain and a structurally conserved ligand-binding domain
The canonical NR family is exclusively found in metazoans and the number of nuclear receptor members varies dramatically depending on species; from 21 NR genes in Drosophila melanogaster, to,50 in rodents and humans, to over 250 NRs in Caenorhabditis elegans and related nematodes [3]
This factor helps manage tube development by regulating genes involved in ion transport and membrane fusion, likely helping to balance the growth of the inner and outer portions of the excretory tube as this structure elongates. This transcription factor shares significant homology with a mammalian protein that participates in hormone signaling and is present in the kidney tubules, suggesting that elongation and growth of tube structures may rely on a new kind of hormonal communication that occurs between distant parts of the cell; this signaling mechanism may be important for appropriate kidney development in humans
Summary
Nuclear receptors (NRs) comprise a large family of transcription factors distinguished by a highly conserved DNA binding domain and a structurally conserved ligand-binding domain. The remaining 268 NRs are thought to be derived from extensive duplication and diversification of an ancestral gene most closely related to the mammalian and Drosophila HNF4 receptors [5] The presence of both highly similar and divergent HNF4-type receptors in nematodes implies that many of these proteins will carry out conserved structural and physiological functions, whereas others will have evolved to adopt responsibilities more specific to the nematode lineage. This idea is supported by the fact the C. elegans NHR-49 nuclear receptor shares many of the metabolic functions of the mammalian HNF4a, but not the developmental activities [6,7]. Study of C. elegans NRs should be helpful for understanding mammalian NR function and physiology, but should reveal novel regulatory activities for the nuclear receptor family
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