All Title Author
Keywords Abstract

PLOS ONE  2012 

Fishing the Molecular Bases of Treacher Collins Syndrome

DOI: 10.1371/journal.pone.0029574

Full-Text   Cite this paper   Add to My Lib

Abstract:

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, and mutations in the TCOF1 gene are responsible for over 90% of TCS cases. The knowledge about the molecular mechanisms responsible for this syndrome is relatively scant, probably due to the difficulty of reproducing the pathology in experimental animals. Zebrafish is an emerging model for human disease studies, and we therefore assessed it as a model for studying TCS. We identified in silico the putative zebrafish TCOF1 ortholog and cloned the corresponding cDNA. The derived polypeptide shares the main structural domains found in mammals and amphibians. Tcof1 expression is restricted to the anterior-most regions of zebrafish developing embryos, similar to what happens in mouse embryos. Tcof1 loss-of-function resulted in fish showing phenotypes similar to those observed in TCS patients, and enabled a further characterization of the mechanisms underlying craniofacial malformation. Besides, we initiated the identification of potential molecular targets of treacle in zebrafish. We found that Tcof1 loss-of-function led to a decrease in the expression of cellular proliferation and craniofacial development. Together, results presented here strongly suggest that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the TCOF1 ortholog in zebrafish. This experimental condition may facilitate the study of the disease etiology during embryonic development.

References

[1]  Passos-Bueno MR, Ornelas CC, Fanganiello RD (2009) Syndromes of the first and second pharyngeal arches: A review. Am J Med Genet A 149A: 1853–1859.
[2]  Dixon J, Dixon MJ (2004) Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle. Dev Dyn 229: 907–914.
[3]  Splendore A, Fanganiello RD, Masotti C, Morganti LS, Passos-Bueno MR (2005) TCOF1 mutation database: novel mutation in the alternatively spliced exon 6A and update in mutation nomenclature. Hum Mutat 25: 429–434.
[4]  Splendore A, Jabs EW, Felix TM, Passos-Bueno MR (2003) Parental origin of mutations in sporadic cases of Treacher Collins syndrome. Eur J Hum Genet 11: 718–722.
[5]  Wise CA, Chiang LC, Paznekas WA, Sharma M, Musy MM, et al. (1997) TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. Proc Natl Acad Sci U S A 94: 3110–3115.
[6]  Marszalek B, Wisniewski SA, Wojcicki P, Kobus K, Trzeciak WH (2003) Novel mutation in the 5′ splice site of exon 4 of the TCOF1 gene in the patient with Treacher Collins syndrome. Am J Med Genet A 123A: 169–171.
[7]  Edwards SJ, Gladwin AJ, Dixon MJ (1997) The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. Am J Hum Genet 60: 515–524.
[8]  Splendore A, Jabs EW, Passos-Bueno MR (2002) Screening of TCOF1 in patients from different populations: confirmation of mutational hot spots and identification of a novel missense mutation that suggests an important functional domain in the protein treacle. J Med Genet 39: 493–495.
[9]  Splendore A, Silva EO, Alonso LG, Richieri-Costa A, Alonso N, et al. (2000) High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat 16: 315–322.
[10]  Gonzales B, Yang H, Henning D, Valdez BC (2005) Cloning and functional characterization of the Xenopus orthologue of the Treacher Collins syndrome (TCOF1) gene product. Gene 359: 73–80.
[11]  Hayano T, Yanagida M, Yamauchi Y, Shinkawa T, Isobe T, et al. (2003) Proteomic analysis of human Nop56p-associated pre-ribosomal ribonucleoprotein complexes. Possible link between Nop56p and the nucleolar protein treacle responsible for Treacher Collins syndrome. J Biol Chem 278: 34309–34319.
[12]  Valdez BC, Henning D, So RB, Dixon J, Dixon MJ (2004) The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc Natl Acad Sci U S A 101: 10709–10714.
[13]  Dixon J, Jones NC, Sandell LL, Jayasinghe SM, Crane J, et al. (2006) Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci U S A 103: 13403–13408.
[14]  Dixon J, Brakebusch C, Fassler R, Dixon MJ (2000) Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum Mol Genet 9: 1473–1480.
[15]  Dixon J, Hovanes K, Shiang R, Dixon MJ (1997) Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1 Hum Mol Genet 6: 727–737.
[16]  Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, et al. (2008) Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med 14: 125–133.
[17]  Parsons KJ, Andreeva V, James CW, Yelick PC, Craig AR (2011) Morphogenesis of the zebrafish jaw: development beyond the embryo. Methods Cell Biol 101: 225–248.
[18]  Schilling TF, Kimmel CB (1997) Musculoskeletal patterning in the pharyngeal segments of the zebrafish embryo. Development 124: 2945–2960.
[19]  Hubbard T, Barker D, Birney E, Cameron G, Chen Y, et al. (2002) The Ensembl genome database project. Nucleic Acids Res 30: 38–41.
[20]  Marsh KL, Dixon J, Dixon MJ (1998) Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle. Hum Mol Genet 7: 1795–1800.
[21]  Winokur ST, Shiang R (1998) The Treacher Collins syndrome (TCOF1) gene product, treacle, is targeted to the nucleolus by signals in its C-terminus. Hum Mol Genet 7: 1947–1952.
[22]  Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294: 1351–1362.
[23]  Duffy KT, McAleer MF, Davidson WR, Kari L, Kari C, et al. (2005) Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids. Nucleic Acids Res 33: 4914–4921.
[24]  Loeb-Hennard C, Kremmer E, Bally-Cuif L (2005) Prominent transcription of zebrafish N-myc (nmyc1) in tectal and retinal growth zones during embryonic and early larval development. Gene Expr Patterns 5: 341–347.
[25]  Weiner AM, Allende ML, Becker TS, Calcaterra NB (2007) CNBP mediates neural crest cell expansion by controlling cell proliferation and cell survival during rostral head development. J Cell Biochem 102: 1553–1570.
[26]  Wullimann MF, Knipp S (2000) Proliferation pattern changes in the zebrafish brain from embryonic through early postembryonic stages. Anat Embryol (Berl) 202: 385–400.
[27]  Nasevicius A, Ekker SC (2000) Effective targeted gene ‘knockdown’ in zebrafish. Nat Genet 26: 216–220.
[28]  Weiner AM, Sdrigotti MA, Kelsh RN, Calcaterra NB (2011) Deciphering the cellular and molecular roles of CNBP during cranial neural crest development. Dev Growth Differ. In press.
[29]  Robu ME, Larson JD, Nasevicius A, Beiraghi S, Brenner C, et al. (2007) p53 activation by knockdown technologies. PLoS Genet 3: e78.
[30]  Steventon B, Carmona-Fontaine C, Mayor R (2005) Genetic network during neural crest induction: from cell specification to cell survival. Semin Cell Dev Biol 16: 647–654.
[31]  Yan YL, Willoughby J, Liu D, Crump JG, Wilson C, et al. (2005) A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial and pectoral fin development. Development 132: 1069–1083.
[32]  Mogass M, York TP, Li L, Rujirabanjerd S, Shiang R (2004) Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma. Biochem Biophys Res Commun 325: 124–132.
[33]  Walker MB, Trainor PA (2006) Craniofacial malformations: intrinsic vs extrinsic neural crest cell defects in Treacher Collins and 22q11 deletion syndromes. Clin Genet 69: 471–479.
[34]  Eberhart JK, Swartz ME, Crump JG, Kimmel CB (2006) Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development. Development 133: 1069–1077.
[35]  Kimmel CB, Miller CT, Moens CB (2001) Specification and morphogenesis of the zebrafish larval head skeleton. Dev Biol 233: 239–257.
[36]  Wada N, Javidan Y, Nelson S, Carney TJ, Kelsh RN, et al. (2005) Hedgehog signaling is required for cranial neural crest morphogenesis and chondrogenesis at the midline in the zebrafish skull. Development 132: 3977–3988.
[37]  Kovacevic Z, Sivagurunathan S, Mangs H, Chikhani S, Zhang D, et al. (2011) The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), upregulates p21 via p53-independent mechanisms. Carcinogenesis 32: 732–740.
[38]  Angst E, Dawson DW, Stroka D, Gloor B, Park J, et al. (2011) N-myc downstream regulated gene-1 expression correlates with reduced pancreatic cancer growth and increased apoptosis in vitro and in vivo. Surgery 149: 614–624.
[39]  Fong SH, Emelyanov A, Teh C, Korzh V (2005) Wnt signalling mediated by Tbx2b regulates cell migration during formation of the neural plate. Development 132: 3587–3596.
[40]  Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, et al. (2000) Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet 26: 291–299.
[41]  Uhlmann-Schiffler H, Kiermayer S, Stahl H (2009) The DEAD box protein Ddx42p modulates the function of ASPP2, a stimulator of apoptosis. Oncogene 28: 2065–2073.
[42]  Armas P, Nasif S, Calcaterra NB (2008) Cellular nucleic acid binding protein binds G-rich single-stranded nucleic acids and may function as a nucleic acid chaperone. J Cell Biochem 103: 1013–1036.
[43]  Borgognone M, Armas P, Calcaterra NB (2010) Cellular nucleic-acid-binding protein, a transcriptional enhancer of c-Myc, promotes the formation of parallel G-quadruplexes. Biochem J 428: 491–498.
[44]  Calcaterra NB, Armas P, Weiner AM, Borgognone M (2010) CNBP: A multifunctional nucleic acid chaperone involved in cell death and proliferation control. IUBMB Life 62: 707–714.
[45]  Armas P, Aguero TH, Borgognone M, Aybar MJ, Calcaterra NB (2008) Dissecting CNBP, a zinc-finger protein required for neural crest development, in its structural and functional domains. J Mol Biol 382: 1043–1056.
[46]  Armas P, Cachero S, Lombardo VA, Weiner A, Allende ML, et al. (2004) Zebrafish cellular nucleic acid-binding protein: gene structure and developmental behaviour. Gene 337: 151–161.
[47]  Tang R, Dodd A, Lai D, McNabb WC, Love DR (2007) Validation of zebrafish (Danio rerio) reference genes for quantitative real-time RT-PCR normalization. Acta Biochim Biophys Sin (Shanghai) 39: 384–390.
[48]  Jowett T, Lettice L (1994) Whole-mount in situ hybridizations on zebrafish embryos using a mixture of digoxigenin- and fluorescein-labelled probes. Trends Genet 10: 73–74.
[49]  Solomon KS, Kudoh T, Dawid IB, Fritz A (2003) Zebrafish foxi1 mediates otic placode formation and jaw development. Development 130: 929–940.

Full-Text

comments powered by Disqus