RESUMEN
Notochord-derived Sonic Hedgehog (Shh) is essential for dorsoventral patterning of the overlying neural tube. Increasing concentration and duration of Shh signal induces progenitors to acquire progressively more ventral fates. We show that Notch signalling augments the response of neuroepithelial cells to Shh, leading to the induction of higher expression levels of the Shh target gene Ptch1 and subsequently induction of more ventral cell fates. Furthermore, we demonstrate that activated Notch1 leads to pronounced accumulation of Smoothened (Smo) within primary cilia and elevated levels of full-length Gli3. Finally, we show that Notch activity promotes longer primary cilia both in vitro and in vivo. Strikingly, these Notch-regulated effects are Shh independent. These data identify Notch signalling as a novel modulator of Shh signalling that acts mechanistically via regulation of ciliary localisation of key components of its transduction machinery.
Asunto(s)
Proteínas Aviares/metabolismo , Cilios/metabolismo , Proteínas Hedgehog/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Biomarcadores/metabolismo , Linaje de la Célula , Embrión de Pollo , Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Neuronas Motoras/metabolismo , Células 3T3 NIH , Proteínas del Tejido Nervioso/metabolismo , Placa Neural/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Tubo Neural/metabolismo , Notocorda/metabolismo , Receptores Notch/antagonistas & inhibidores , Receptor Smoothened , Proteína Gli3 con Dedos de ZincRESUMEN
BACKGROUND: ERK5 is a member of the mitogen activated protein kinase family activated by certain mitogenic or stressful stimuli in cells, but whose physiological role is largely unclear. RESULTS: To help determine the function of ERK5 we have used gene targeting to inactivate this gene in mice. Here we report that ERK5 knockout mice die at approximately E10.5. In situ hybridisation for ERK5, and its upstream activator MKK5, showed strong expression in the head and trunk of the embryo at this stage of development. Between E9.5 and E10.5, multiple developmental problems are seen in the ERK5-/- embryos, including an increase in apoptosis in the cephalic mesenchyme tissue, abnormalities in the hind gut, as well as problems in vascular remodelling, cardiac development and placental defects. CONCLUSION: Erk5 is essential for early embryonic development, and is required for normal development of the vascular system and cell survival.