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1.
PLoS Genet ; 7(10): e1002335, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22022287

RESUMO

Ciliopathies are pleiotropic and genetically heterogeneous disorders caused by defective development and function of the primary cilium. Bardet-Biedl syndrome (BBS) proteins localize to the base of cilia and undergo intraflagellar transport, and the loss of their functions leads to a multisystemic ciliopathy. Here we report the identification of mutations in guanylate cyclases (GCYs) as modifiers of Caenorhabditis elegans bbs endophenotypes. The loss of GCY-35 or GCY-36 results in suppression of the small body size, developmental delay, and exploration defects exhibited by multiple bbs mutants. Moreover, an effector of cGMP signalling, a cGMP-dependent protein kinase, EGL-4, also modifies bbs mutant defects. We propose that a misregulation of cGMP signalling, which underlies developmental and some behavioural defects of C. elegans bbs mutants, may also contribute to some BBS features in other organisms.


Assuntos
Síndrome de Bardet-Biedl/genética , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Proteínas Quinases Dependentes de GMP Cíclico/genética , Guanilato Ciclase/genética , Proteínas do Tecido Nervoso/genética , Animais , Animais Geneticamente Modificados , Síndrome de Bardet-Biedl/metabolismo , Tamanho Corporal/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cílios/genética , Cílios/metabolismo , GMP Cíclico/genética , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Guanilato Ciclase/metabolismo , Humanos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Transporte Proteico/genética , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/genética
2.
J Cell Sci ; 122(Pt 5): 611-24, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19208769

RESUMO

Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms. Consistent with a ciliary role, all Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia. Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins. This localization is evolutionarily conserved, because the human orthologues also localize to basal bodies, as well as cilia. As reported for MKS1, disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. By contrast, single, double and triple C. elegans mks/mksr mutants do not display overt defects in ciliary structure, intraflagellar transport or chemosensation. However, we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling. Our findings therefore demonstrate functional interactions between a novel family of proteins associated with basal bodies or cilia, providing new insights into the molecular etiology of a pleiotropic human disorder.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Cílios/patologia , Proteínas/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/classificação , Proteínas de Caenorhabditis elegans/genética , Cílios/metabolismo , Evolução Molecular , Humanos , Dados de Sequência Molecular , Fenótipo , Filogenia , Proteínas/classificação , Proteínas/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Transdução de Sinais/fisiologia
3.
PLoS Genet ; 4(3): e1000044, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18369462

RESUMO

MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Flagelos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Animais Geneticamente Modificados , Sequência de Bases , Transporte Biológico Ativo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Cílios/fisiologia , Primers do DNA/genética , DNA de Helmintos/genética , Genes de Helmintos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/fisiologia , Morfogênese , Complexos Multiproteicos , Mutação , Neurônios Aferentes/fisiologia , Fenótipo , Transdução de Sinais
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