title: NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways.
abstract: Mutations in the human NPC1 gene cause most cases of Niemann-Pick type C (NP-C) disease, a fatal autosomal recessive neurodegenerative disorder. NPC1 is implicated in intracellular trafficking of cholesterol and glycolipids, but its exact function remains unclear. The C. elegans genome contains two homologs of NPC1, ncr-1 and ncr-2, and an ncr-2; ncr-1 double deletion mutant forms dauer larvae constitutively (Daf-c). We have analyzed the phenotypes of ncr single and double mutants in detail, and determined the ncr gene expression patterns. We find that the ncr genes function in a hormonal branch of the dauer formation pathway upstream of daf-9 and daf-12, which encode a cytochrome P450 enzyme and a nuclear hormone receptor, respectively. ncr-1 is expressed broadly in tissues with high levels of cholesterol, whereas expression of ncr-2 is restricted to a few cells. Both Ncr genes are expressed in the XXX cells, which are implicated in regulating dauer formation via the daf-9 pathway. Only the ncr-1 mutant is hypersensitive to cholesterol deprivation and to progesterone, an inhibitor of intracellular cholesterol trafficking. Our results support the hypothesis that ncr-1 and ncr-2 are involved in intracellular cholesterol processing in C. elegans, and that a sterol-signaling defect is responsible for the Daf-c phenotype of the ncr-2; ncr-1 mutant.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Gemma
authors.initials: G
authors.lastname: Brown
authors.forename: Michael
authors.initials: M
authors.lastname: Ailion
authors.forename: Samuel
authors.initials: S
authors.lastname: Lee
authors.forename: James H
authors.initials: JH
authors.lastname: Thomas
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D002784:Cholesterol / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D010641:Phenotype; D011374:Progesterone / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003470:Culture Media; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C495203:NCR-1 protein, C elegans; C495204:NCR-2 protein, C elegans; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C486228:DAF-9 protein, C elegans; D017027:Protein Tyrosine Phosphatases; C476241:SDF-9 protein, C elegans