NHR-23, a conserved member of the nuclear receptor family of transcription factors, is required for normal development in Caenorhabditis elegans where it plays a critical role in growth and molting. In a search for NHR-23 dependent genes, we performed whole genome comparative expression microarrays on both control and nhr-23 inhibited synchronized larvae. Genes that decreased in response to nhr-23 RNAi included several collagen genes. Unexpectedly, several hedgehog-related genes were also down-regulated after nhr-23 RNAi. A homozygous nhr-23 deletion allele was used to confirm the RNAi knockdown phenotypes and the changes in gene expression. Our results indicate that NHR-23 is a critical co-regulator of functionally linked genes involved in growth and molting and reveal evolutionary parallels among the ecdysozoa.

Laboratory of Model Systems Institute of Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Huet F, Ruiz C, Richards G. Sequential gene activation by ecdysone in Drosophila melanogaster: the hierarchical equivalence of early and early late genes. Development. 1995;121:1195–1204. PubMed

Lam G, Hall BL, Bender M, Thummel CS. DHR3 is required for the prepupalpupal transition and differentiation of adult structures during Drosophila metamorphosis. Dev Biol. 1999;212:204–216. PubMed

Schubiger M, Carre C, Antoniewski C, Truman JW. Ligand-dependent derepression via EcR/USP acts as a gate to coordinate the differentiation of sensory neurons in the Drosophila wing. Development. 2005;132:5239–5248. PubMed

Schubiger M, Tomita S, Sung C, Robinow S, Truman JW. Isoform specific control of gene activity in vivo by the Drosophila ecdysone receptor. Mech Dev. 2003;120:909–918. PubMed

Ghbeish N, Tsai CC, Schubiger M, Zhou JY, Evans RM, McKeown M. The dual role of ultraspiracle, the Drosophila retinoid X receptor, in the ecdysone response. Proc Natl Acad Sci U S A. 2001;98:3867–3872. PubMed PMC

Schubiger M, Truman JW. The RXR ortholog USP suppresses early metamorphic processes in Drosophila in the absence of ecdysteroids. Development. 2000;127:1151–1159. PubMed

Schubiger M, Wade AA, Carney GE, Truman JW, Bender M. Drosophila EcRB ecdysone receptor isoforms are required for larval molting and for neuron remodeling during metamorphosis. Development. 1998;125:2053–2062. PubMed

Dunn CW, Hejnol A, Matus DQ, Pang K, Browne WE, Smith SA, Seaver E, Rouse GW, Obst M, Edgecombe GD, Sorensen MV, Haddock SH, Schmidt-Rhaesa A, Okusu A, Kristensen RM, Wheeler WC, Martindale MQ, Giribet G. Broad phylogenomic sampling improves resolution of the animal tree of life. Nature. 2008;452:745–749. PubMed

King-Jones K, Thummel CS. Nuclear receptors--a perspective from Drosophila. Nat Rev Genet. 2005;6:311–323. PubMed

Carney GE, Wade AA, Sapra R, Goldstein ES, Bender M. DHR3, an ecdysone-inducible early-late gene encoding a Drosophila nuclear receptor, is required for embryogenesis. Proc Natl Acad Sci U S A. 1997;94:12024–12029. PubMed PMC

Lam GT, Jiang C, Thummel CS. Coordination of larval and prepupal gene expression by the DHR3 orphan receptor during Drosophila metamorphosis. Development. 1997;124:1757–1769. PubMed

Kostrouchova M, Krause M, Kostrouch Z, Rall JE. CHR3: a Caenorhabditis elegans orphan nuclear hormone receptor required for proper epidermal development and molting. Development. 1998;125:1617–1626. PubMed

Kostrouchova M, Krause M, Kostrouch Z, Rall JE. Nuclear hormone receptor CHR3 is a critical regulator of all four larval molts of the nematode Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2001;98:7360–7365. PubMed PMC

Hayes GD, Frand AR, Ruvkun G. The mir-84 and let-7 paralogous microRNA genes of Caenorhabditis elegans direct the cessation of molting via the conserved nuclear hormone receptors NHR-23 and NHR-25. Development. 2006;133:4631–4641. PubMed

Bethke A, Fielenbach N, Wang Z, Mangelsdorf DJ, Antebi A. Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science. 2009;324:95–98. PubMed PMC

Yochem J, Tuck S, Greenwald I, Han M. A gp330/megalin-related protein is required in the major epidermis of Caenorhabditis elegans for completion of molting. Development. 1999;126:597–606. PubMed

Aspock G, Kagoshima H, Niklaus G, Burglin TR. Caenorhabditis elegans has scores of hedgehog-related genes: sequence and expression analysis. Genome Res. 1999;9:909–923. PubMed

Hao L, Aspock G, Burglin TR. The hedgehog-related gene wrt-5 is essential for hypodermal development in Caenorhabditis elegans. Dev Biol. 2006;290:323–336. PubMed

Hao L, Johnsen R, Lauter G, Baillie D, Burglin TR. Comprehensive analysis of gene expression patterns of hedgehog-related genes. BMC Genomics. 2006;7:280. PubMed PMC

Hao L, Mukherjee K, Liegeois S, Baillie D, Labouesse M, Burglin TR. The hedgehog-related gene qua-1 is required for molting in Caenorhabditis elegans. Dev Dyn. 2006;235:1469–1481. PubMed

Burglin TR, Kuwabara PE. Homologs of the Hh signalling network in C. elegans. WormBook. 2006:1–14. PubMed PMC

Burglin TR. The Hedgehog protein family. Genome Biol. 2008;9:241. PubMed PMC

Burglin TR. Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif. BMC Genomics. 2008;9:127. PubMed PMC

Zugasti O, Rajan J, Kuwabara PE. The function and expansion of the Patched-and Hedgehog-related homologs in C. elegans. Genome Res. 2005;15:1402–1410. PubMed PMC

Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77:71–94. PubMed PMC

Vohanka J, Simeckova K, Machalova E, Behensky F, Krause MW, Kostrouch Z, Kostrouchova M. Diversification of fasting regulated transcription in a cluster of duplicated nuclear hormone receptors in C. elegans. Gene Expr Patterns. 2010;10:227–236. PubMed PMC

Huang D, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57. PubMed

Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13. PubMed PMC

Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994;8:538–553. PubMed

Akiyama Y. TFSEARCH: Searching Transcription Factor Binding Sites, based on the TRANSFAC databases (ref. 33) [August 5, 2011];1998 Date of the last accession http://www.cbrc.jp/research/db/TFSEARCH.html.

Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, Podkolodny NL, Kolchanov NA. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res. 1998;26:362–367. PubMed PMC

Odenwald WF, Rasband W, Kuzin A, Brody T. EVOPRINTER, a multigenomic comparative tool for rapid identification of functionally important DNA. Proc Natl Acad Sci U S A. 2005;102:14700–14705. PubMed PMC

Maryon EB, Coronado R, Anderson P. unc-68 encodes a ryanodine receptor involved in regulating C. elegans body-wall muscle contraction. J Cell Biol. 1996;134:885–893. PubMed PMC

Maryon EB, Saari B, Anderson P. Muscle-specific functions of ryanodine receptor channels in Caenorhabditis elegans. J Cell Sci. 1998;111(Pt 19):2885–2895. PubMed

Mercer KB, Flaherty DB, Miller RK, Qadota H, Tinley TL, Moerman DG, Benian GM. Caenorhabditis elegans UNC-98, a C2H2 Zn finger protein, is a novel partner of UNC-97/PINCH in muscle adhesion complexes. Mol Biol Cell. 2003;14:2492–2507. PubMed PMC

Watanabe N, Nagamatsu Y, Gengyo-Ando K, Mitani S, Ohshima Y. Control of body size by SMA-5, a homolog of MAP kinase BMK1/ERK5, in C. elegans. Development. 2005;132:3175–3184. PubMed

McMahon L, Muriel JM, Roberts B, Quinn M, Johnstone IL. Two sets of interacting collagens form functionally distinct substructures within a Caenorhabditis elegans extracellular matrix. Mol Biol Cell. 2003;14:1366–1378. PubMed PMC

Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron. 2003;40:1119–1131. PubMed PMC