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El eje de señalización RIPK4-IRF6 protege la diferenciación epidérmica y la función de barrera
Nina Oberbeck1, Victoria C Pham2, Joshua D Webster3
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|October 4, 2019
Resumen
La quinasa RIPK4 y el factor de transcripción IRF6 son cruciales para la función de la barrera epidérmica. Su acción coordinada asegura el desarrollo adecuado de la piel, y los defectos conducen a anormalidades graves del desarrollo.
Área de la Ciencia:
- Biología del desarrollo
- Biología molecular
- La genética
Sus antecedentes:
- La integridad de la epidermis de los mamíferos depende de la proliferación y diferenciación de las células madre.
- Las mutaciones en RIPK4 e IRF6 causan síndromes de desarrollo con defectos epidérmicos.
- Los roles precisos de RIPK4 e IRF6 en la diferenciación epidérmica no se comprenden completamente.
Objetivo del estudio:
- Aclarar los mecanismos por los cuales RIPK4 e IRF6 regulan la diferenciación epidérmica.
- Definir los programas de transcripción controlados por IRF6 en la epidermis en desarrollo.
- Comprender las consecuencias funcionales de la deficiencia de IRF6 en la formación de la barrera epidérmica.
Principales métodos:
- Se utilizó la secuenciación de ARN (RNA-seq), ChIP-seq y ATAC-seq en embriones de ratón de tipo salvaje y con deficiencia de IRF6.
- Investigó el requisito de actividad de la quinasa para RIPK4 en desarrollo.
- Se analizaron los sitios de fosforilación de IRF6 críticos para su activación.
Principales resultados:
- La actividad de la cinasa RIPK4 es esencial para el desarrollo del ratón.
- RIPK4 e IRF6 regulan los procesos biológicos comunes en la epidermis.
- La fosforilación IRF6 en Ser413 y Ser424 lo prepara para la activación.
- La deficiencia de IRF6 afecta a los genes implicados en el metabolismo de los lípidos y en la formación de uniones estrechas.
- Los ratones Irf6-/- presentan una composición lipídica anormal del estrato córneo y defectos de la barrera epidérmica.
Conclusiones:
- RIPK4 e IRF6 son reguladores clave de la integridad epidérmica a través del control coordinado de la diferenciación.
- Los defectos en el eje RIPK4-IRF6 explican los síndromes de desarrollo que afectan el desarrollo orofacial, cutáneo y genital.
- La fosforilación de IRF6 es un paso crítico en su vía de activación durante el desarrollo epidérmico.
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