RESUMO
The ciliopathies are a class of rare human genetic disease whose aetioligies lie in defective primary cilia. Typical ciliopathies include Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Jeune, Joubert, oro-facial-digital (OFD1) and Meckel (MKS) syndromes. All ciliopathies have the common denominator of renal disease, often including tubular cysts. In this study, we have modelled a range of ciliopathies in zebrafish and shown in all cases that knocking down these genes causes cystic lesions in the kidney. We have identified two drugs, rapamycin and roscovitine, which ameliorate the renal phenotype, both morphologically and functionally. This is the first study in which zebrafish has been used to identify potential therapeutic modalities for ciliopathic renal disease, and the results pave the way for further investigations in mammalian models.
Assuntos
Antineoplásicos/farmacologia , Imunossupressores/farmacologia , Doenças Renais Policísticas/tratamento farmacológico , Purinas/farmacologia , Sirolimo/farmacologia , Animais , Síndrome de Bardet-Biedl/tratamento farmacológico , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/patologia , Cílios/patologia , Modelos Animais de Doenças , Rim/fisiologia , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Roscovitina , Peixe-ZebraRESUMO
Primary (nonmotile) cilia are currently enjoying a renaissance in light of novel ascribed functions ranging from mechanosensory to signal transduction. Their importance for key developmental pathways such as Sonic Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal cilia, for example, is vital for breaking early embryonic symmetry, Shh signaling is important for tissue morphogenesis and successful Wnt signaling for organ growth and differentiation. When ciliary function is perturbed, photoreceptors may die, kidney tubules develop cysts, limb digits multiply and brains form improperly. The etiology of several uncommon disorders has recently been associated with cilia dysfunction. The causative genes are often similar and their cognate proteins certainly share cellular locations and/or pathways. Animal models of ciliary gene ablation such as Ift88, Kif3a, and Bbs have been invaluable for understanding the broad function of the cilium. Herein, we describe the wealth of information derived from the study of the ciliopathies and their animal models.
Assuntos
Anormalidades Múltiplas/patologia , Cílios/patologia , Cílios/fisiologia , Modelos Animais de Doenças , Camundongos , Anormalidades Múltiplas/genética , Animais , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/patologia , Padronização Corporal/genética , Cistos/genética , Cistos/patologia , Cistos/terapia , Doença/etiologia , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Humanos , Camundongos Transgênicos , Modelos Biológicos , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , SíndromeRESUMO
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.
Assuntos
Asfixia/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Doenças Renais Císticas/genética , Mutação/genética , Tetrahymena thermophila/genética , Doenças Torácicas/genética , Peixe-Zebra/genética , Animais , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Polidactilia/genética , Tetrahymena thermophila/crescimento & desenvolvimento , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
The Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis. The study of this multi-system disorder, which includes obesity, cognitive impairment, genito-urinary tract malformations and limb deformities, is beginning to reveal insights into several aspects of mammalian development and organogenesis. Involvement of BBS proteins in disparate pathways such as the non-canonical Wnt and Sonic Hedgehog pathways is highlighting their interplay in disease pathogenesis. Here we review the recent developments in this emerging field, with the emphasis on the renal component of the syndrome and potential future directions.