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La señalización de Norrin, frizzled-4 y Lrp5 en las células endoteliales controla un programa genético para la
Xin Ye1, Yanshu Wang, Hugh Cahill
1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell
|October 20, 2009
Resumen
La señalización de Norrin/Frizzled-4 (Fz4) es crucial para el desarrollo vascular. La pérdida de Fz4 en las células endoteliales afecta el crecimiento de los vasos sanguíneos, lo que lleva a la disfunción de las neuronas de la retina y posibles problemas vasculares del sistema nervioso central.
Área de la Ciencia:
- Biología vascular Biología vascular
- La neurociencia es la neurociencia.
- Biología del desarrollo Biología del desarrollo.
Sus antecedentes:
- La estructura y la función vasculares son críticas en las enfermedades del sistema nervioso central (SNC).
- Las mutaciones en Frizzled-4 (Fz4), Lrp5 o Norrin causan hipovascularización retiniana, pero los mecanismos subyacentes no están claros.
Objetivo del estudio:
- Definir los mecanismos por los cuales la señalización Norrin/Fz4/Lrp controla el desarrollo vascular.
- Para investigar la base celular de las enfermedades de hipovascularización de la retina.
Principales métodos:
- Se utilizaron modelos genéticos de ratón y cultivos celulares.
- Se analizó el papel de la señalización de Frizzled-4 (Fz4) en las células endoteliales.
- Investigó la función del factor de transcripción Sox17.
Principales resultados:
- La pérdida de la señalización de Fz4 en las células endoteliales dio lugar a un crecimiento vascular defectuoso y a un silenciamiento reversible de las neuronas de la retina.
- La interrupción de Fz4 en las células endoteliales comprometió la barrera hematoencefálica en el cerebelo.
- La excesiva señalización de Fz4 interrumpió la angiogénesis embrionaria.
- Sox17, regulado al alza por la señalización de Norrin/Fz4/Lrp, es fundamental para el programa angiogénico.
Conclusiones:
- Se estableció una base celular para las enfermedades de hipovascularización de la retina vinculadas a una insuficiente señalización Frizzled.
- Sugiere un papel más amplio para la señalización de Frizzled en el crecimiento vascular, remodelación, mantenimiento y enfermedad.
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