Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
PLoS One ; 7(10): e47168, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23071748

RESUMEN

In vitro studies have identified LIMK2 as a key downstream effector of Rho GTPase-induced changes in cytoskeletal organization. LIMK2 is phosphorylated and activated by Rho associated coiled-coil kinases (ROCKs) in response to a variety of growth factors. The biochemical targets of LIMK2 belong to a family of actin binding proteins that are potent modulators of actin assembly and disassembly. Although numerous studies have suggested that LIMK2 regulates cell morphology and motility, evidence supportive of these functions in vivo has remained elusive. In this study, a knockout mouse was created that abolished LIMK2 biochemical activity resulting in a profound inhibition of epithelial sheet migration during eyelid development. In the absence of LIMK2, nascent eyelid keratinocytes differentiate and acquire a pre-migratory phenotype but the leading cells fail to nucleate filamentous actin and remain immobile causing an eyes open at birth (EOB) phenotype. The failed nucleation of actin was associated with significant reductions in phosphorylated cofilin, a major LIMK2 biochemical substrate and potent modulator of actin dynamics. These results demonstrate that LIMK2 activity is required for keratinocyte migration in the developing eyelid.


Asunto(s)
Movimiento Celular/genética , Párpados/citología , Queratinocitos/citología , Quinasas Lim/fisiología , Actinas/metabolismo , Animales , Párpados/embriología , Párpados/patología , Genotipo , Quinasas Lim/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Fosforilación
2.
Invest Ophthalmol Vis Sci ; 52(9): 6452-61, 2011 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-21743011

RESUMEN

PURPOSE. Mice deficient in the secreted protein Norrin or its receptor Frizzled-4 (FZD4) exhibit incomplete vascularization of the neural retina. However, because of early retinal vascular defects in the knockout models, it has not been possible to study FZD4 contribution in ocular neovascular disease. To further understand the role of this signaling pathway in physiological and pathologic angiogenesis, the authors generated a monoclonal antibody that neutralizes FZD4 function in vivo. METHODS. Antibodies were generated by immunizing Fzd4 knockout mice with the cysteine-rich domain of FZD4. A monoclonal antibody (1.99.25) was discovered that antagonizes Norrin- and WNT3A-induced ß-catenin accumulation in vitro. 1.99.25 and an isotype-matched negative control antibody were evaluated in models of developmental retinal angiogenesis, oxygen-induced retinopathy, and retinal angiomatous proliferation. The authors also investigated the role of FZD4 in maintaining the blood-retina barrier in normal adult mice. RESULTS. Administration of 1.99.25 inhibited physiological and pathologic sprouting angiogenesis within the retina. Inhibition of FZD4 in developing retinal vascular networks caused the upregulation of PLVAP, a protein normally associated with fenestrated, immature endothelium in the CNS. In the adult neural retina, the administration of 1.99.25 induced PLVAP expression in the deep capillary bed and enabled extravasation of small and large molecules through the blood-retina barrier. CONCLUSIONS. These results demonstrate that FZD4 is required for physiological and pathologic angiogenesis in the retina and for regulation of retinal endothelial cell differentiation. The authors also show that FZD4 is critical for maintaining the integrity of the mature blood-retina barrier.


Asunto(s)
Barrera Hematorretinal/fisiología , Modelos Animales de Enfermedad , Receptores Frizzled/fisiología , Neovascularización Fisiológica/fisiología , Receptores Acoplados a Proteínas G/fisiología , Neovascularización Retiniana/metabolismo , Animales , Animales Recién Nacidos , Anticuerpos Neutralizantes/farmacología , Permeabilidad Capilar/fisiología , Proteínas del Ojo/antagonistas & inhibidores , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Receptores Frizzled/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Fisiológica/efectos de los fármacos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Oxígeno/toxicidad , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de LDL/metabolismo , Neovascularización Retiniana/inducido químicamente , Neovascularización Retiniana/prevención & control , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/fisiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA