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
Hensen's node of the chick embryo contains multipotent self-renewing progenitor cells that can contribute to either the floor plate or the notochord. Floor plate cells are a population of epithelial cells that lie at the ventral midline of the developing neural tube, whereas the notochord is a rod of axial mesoderm that lies directly beneath the floor plate. These two tissues serve as a source of a potent signalling morphogen, sonic hedgehog (Shh), which patterns the dorsoventral axis of the neural tube. We show, through both gain- and loss-of-function approaches, that Notch signalling promotes the contribution of chick axial progenitor cells to the floor plate and inhibits contribution to the notochord. Thus, we propose that Notch regulates the allocation of appropriate numbers of progenitor cells from Hensen's node of the chick embryo to the notochord and the floor plate.