title: A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo.
abstract: 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.
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Stasiulewicz
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Shona D
authors.initials: SD
authors.lastname: Gray
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mastromina
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Joana C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Mia
authors.initials: M
authors.lastname: Björklund
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK The Danish Stem Cell Center, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Seymour
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Booth
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Calum
authors.initials: C
authors.lastname: Thompson
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Green
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK MRC Human Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Hall
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK The Danish Stem Cell Center, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK j.k.dale@dundee.ac.uk.
authors.forename: J Kim
authors.initials: JK
authors.lastname: Dale
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D002642:Chick Embryo; D002923:Cilia / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054258:Neural Plate / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D054259:Neural Tube / Q000378:metabolism; D009672:Notochord / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000074290:Zinc Finger Protein Gli3
chemical_list: D030161:Avian Proteins; D015415:Biomarkers; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000074290:Zinc Finger Protein Gli3
keywords: Chick; Cilia; Embryo; Floor plate; Mouse; Notch; Notochord; P3 progenitors; Shh