title: Dishevelled limits Notch signalling through inhibition of CSL.
abstract: Notch and Wnt are highly conserved signalling pathways that are used repeatedly throughout animal development to generate a diverse array of cell types. However, they often have opposing effects on cell-fate decisions with each pathway promoting an alternate outcome. Commonly, a cell receiving both signals exhibits only Wnt pathway activity. This suggests that Wnt inhibits Notch activity to promote a Wnt-ON/Notch-OFF output; but what might underpin this Notch regulation is not understood. Here, we show that Wnt acts via Dishevelled to inhibit Notch signalling, and that this crosstalk regulates cell-fate specification in vivo during Xenopus development. Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. giovanna.collu@mssm.edu
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Collu
authors.forename: Ana
authors.initials: A
authors.lastname: Hidalgo-Sastre
authors.forename: Ahmet
authors.initials: A
authors.lastname: Acar
authors.forename: Laura
authors.initials: L
authors.lastname: Bayston
authors.forename: Clara
authors.initials: C
authors.lastname: Gildea
authors.forename: Michael K
authors.initials: MK
authors.lastname: Leverentz
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mills
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Owens
authors.forename: Olivier
authors.initials: O
authors.lastname: Meurette
authors.forename: Karel
authors.initials: K
authors.lastname: Dorey
authors.forename: Keith
authors.initials: K
authors.lastname: Brennan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000072261:Dishevelled Proteins; D004817:Epidermis / Q000196:embryology; D057809:HEK293 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D014981:Xenopus / Q000196:embryology*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D010750:Phosphoproteins; D051880:Receptors, Notch; D051153:Wnt Proteins; D029867:Xenopus Proteins