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1.
PLoS Genet ; 6(4): e1000907, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20419147

RESUMEN

Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease.


Asunto(s)
Embrión no Mamífero/metabolismo , Proteínas de la Matriz Extracelular/genética , Síndrome de Frasier/genética , Furina/genética , Mutación , Proproteína Convertasas/genética , Proteínas de Pez Cebra/genética , Pez Cebra/embriología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Proteínas de la Matriz Extracelular/metabolismo , Furina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ratones , Datos de Secuencia Molecular , Proproteína Convertasas/metabolismo , Proteínas de Pez Cebra/metabolismo
2.
Dev Biol ; 295(1): 194-205, 2006 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-16678149

RESUMEN

Endothelin1 (Edn1) signaling promotes ventral character to the facial skeleton. In zebrafish edn1 mutants, the ventral jaw structures are severely reduced and fused to their dorsal counterparts, with a loss of joints that normally form at an intermediate dorsal-ventral position. Loss of function at another locus, sturgeon, also yields joint losses, but only mild reductions in the ventral jaw structures. We show that sturgeon encodes one of two orthologs of Furin present in zebrafish, and that both furin genes may function partially redundantly to activate Edn1 signaling. Supporting this hypothesis, early expression of edn1-dependent genes is downregulated in sturgeon (furinA) mutants. Later in development, expression of most of these genes recovers to near wild-type levels in furinA mutants but not in edn1 mutants. The recovery explains the less severe furinA mutant skeletal phenotype and suggests that late gene expression is dependent on a critical level of Edn1 signaling not present in the more severe edn1 mutants. However, expression defects in the intermediate joint-forming domains in both mutants persist, explaining the joint losses observed later in both mutants. We further show that in both mutants the arches fail to correctly undergo ventral elongation before skeletogenesis begins and propose a model in which this failure is largely responsible for the loss of an Edn1-dependent compartmentation of the arch into the intermediate and ventral domains.


Asunto(s)
Tipificación del Cuerpo/fisiología , Endotelina-1/metabolismo , Furina/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Secuencia de Aminoácidos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Mapeo Cromosómico , Embrión no Mamífero/metabolismo , Endotelina-1/genética , Extremidades/embriología , Femenino , Furina/genética , Duplicación de Gen , Regulación del Desarrollo de la Expresión Génica , Proteínas HMGB/genética , Proteínas HMGB/metabolismo , Cabeza/embriología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Datos de Secuencia Molecular , Mutación , Factor de Transcripción SOX9 , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/genética , Proteínas de Pez Cebra/genética
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