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1.
Science ; 293(5537): 2080-4, 2001 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-11486055

RESUMO

One of the most dominant influences in the patterning of multicellular embryos is exerted by the Hedgehog (Hh) family of secreted signaling proteins. Here, we identify a segment polarity gene in Drosophila melanogaster, skinny hedgehog (ski), and show that its product is required in Hh-expressing cells for production of appropriate signaling activity in embryos and in the imaginal precursors of adult tissues. The ski gene encodes an apparent acyltransferase, and we provide genetic and biochemical evidence that Hh proteins from ski mutant cells retain carboxyl-terminal cholesterol modification but lack amino-terminal palmitate modification. Our results suggest that ski encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of Hh, and further demonstrate that this lipid modification is required for the embryonic and larval patterning activities of the Hh signal.


Assuntos
Aciltransferases/genética , Aciltransferases/metabolismo , Proteínas de Drosophila , Drosophila melanogaster/genética , Proteínas de Insetos/metabolismo , Ácido Palmítico/metabolismo , Transdução de Sinais , Acilação , Aciltransferases/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Padronização Corporal , Colesterol/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Expressão Gênica , Genes de Insetos , Proteínas Hedgehog , Proteínas de Insetos/química , Proteínas de Insetos/genética , Dados de Sequência Molecular , Mutação , Estrutura Terciária de Proteína , Transgenes
2.
Genomics ; 68(1): 30-40, 2000 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10950924

RESUMO

To contribute to the development of the transcription map of human chromosome 21 (HC21), we isolated a new transcript, C21orf5 (chromosome 21 open reading frame 5), encoding a predicted 2298-amino-acid protein. Analysis of the genomic DNA sequence revealed that C21orf5 consists of 37 exons that extend over 130 kb and maps between the CBR3 (carbonyl reductase 3) and the KIAA0136 genes. Northern blot analyses showed a ubiquitously expressed RNA species of 8.5 kb. RNA in situ hybridization on brain sections of normal human embryos revealed a strong labeling in restricted areas of the cerebral cortex. In silico analysis of the deduced C21orf5 protein revealed several highly probable transmembrane segments but no known protein domains or homology with known proteins. However, there were significant homologies to several hypothetical Caenorhabditis elegans proteins and Drosophila melanogaster genomic sequences. To investigate the function of C21orf5, we isolated the cDNA of the C. elegans ortholog and performed double-stranded RNA-mediated genetic interference experiments. The major phenotype observed in the progeny of injected animals was embryonic lethality. Most of the tissues of the embryo failed to undergo proper patterning during gastrulation, and morphogenesis did not occur; thus we termed the ortholog pad-1, for patterning defective 1. These results indicated that pad-1 is essential for the development and the survival of C. elegans. This study provides the first example of the use of C. elegans as a model to study the function of genes on human chromosome 21 that might be involved in Down syndrome.


Assuntos
Padronização Corporal/genética , Caenorhabditis elegans/genética , Cromossomos Humanos Par 21/genética , Proteínas de Membrana/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Padronização Corporal/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/embriologia , Proteínas de Caenorhabditis elegans , DNA Complementar/química , DNA Complementar/genética , Embrião de Mamíferos/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Éxons , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes/genética , Humanos , Hibridização In Situ , Íntrons , Masculino , Dados de Sequência Molecular , RNA de Cadeia Dupla/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Proteínas de Transporte Vesicular
3.
Genomics ; 48(1): 12-23, 1998 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-9503011

RESUMO

The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and mental retardation. Cosmid contigs covering 80% of the region were constructed and EcoRI maps produced. These cosmids were used for exon trapping and cDNA selection from three cDNA libraries (fetal brain, fetal liver, and adult skeletal muscle). Isolated exons and cDNAs were mapped on the EcoRI map, organized into contigs, sequenced, and used as probes for Northern blot analysis of RNA from fetal and adult tissues. We identified 27 genuine or highly probable transcriptional units evenly distributed along the CBR-ERG region. Eight of the transcriptional units are known genes.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 21 , Síndrome de Down/genética , Transcrição Gênica , Cromossomos Artificiais de Levedura , Cosmídeos , DNA Complementar , Éxons , Humanos , Sitios de Sequências Rotuladas
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