MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.
Circ Res
; 107(11): 1336-44, 2010 Nov 26.
Article
en En
| MEDLINE
| ID: mdl-20947829
RATIONALE: Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular endothelial cells during embryonic development, but the mechanisms of their regulation are incompletely understood. OBJECTIVE: To identify microRNAs regulating aspects of the Slit-Robo pathway and vascular patterning. METHODS AND RESULTS: Here, we provide evidence that microRNA (miR)-218, which is encoded by an intron of the Slit genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5-epimerase (GLCE), and that an intact miR-218-Slit-Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal endothelial cell migration, and reduced complexity of the retinal vasculature. CONCLUSIONS: Our findings link Slit gene expression to the posttranscriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Vasos Retinianos
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Glicoproteínas
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Receptores Inmunológicos
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Transducción de Señal
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MicroARNs
/
Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Circ Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos