title: GEI-8, a homologue of vertebrate nuclear receptor corepressor NCoR/SMRT, regulates gonad development and neuronal functions in Caenorhabditis elegans.
abstract: NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide:quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA class. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function.
authors.affiliation: Laboratory of Molecular Biology and Genetics, Institute of Cellular Biology and Pathology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Mikoláš
authors.forename: Johana
authors.initials: J
authors.lastname: Kollárová
authors.forename: Kateřina
authors.initials: K
authors.lastname: Sebková
authors.forename: Vladimír
authors.initials: V
authors.lastname: Saudek
authors.forename: Petr
authors.initials: P
authors.lastname: Yilma
authors.forename: Markéta
authors.initials: M
authors.lastname: Kostrouchová
authors.forename: Michael W
authors.initials: MW
authors.lastname: Krause
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kostrouch
authors.forename: Marta
authors.initials: M
authors.lastname: Kostrouchová
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D056970:Co-Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006066:Gonads / Q000254:growth & development*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D029742:Caenorhabditis elegans Proteins; D056970:Co-Repressor Proteins; C583180:GEI-8 protein, C elegans; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear