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Development 139 (23): 4405-4415

RESEARCH ARTICLES

Dishevelled limits Notch signalling through inhibition of CSL

Giovanna M. Collu1,2,{ddagger}, Ana Hidalgo-Sastre1, Ahmet Acar1,*, Laura Bayston1,*, Clara Gildea1,*, Michael K. Leverentz1,*, Christopher G. Mills1,*, Thomas W. Owens1,*, Olivier Meurette3, Karel Dorey4,{ddagger}, and Keith Brennan1,{ddagger}

1 Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
2 Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1020, New York, NY 10029, USA
3 Apoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
4 The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK

{ddagger} Authors for correspondence (giovanna.collu{at}mssm.edu; karel.dorey{at}manchester.ac.uk; keith.brennan{at}manchester.ac.uk)

Accepted for publication 3 September 2012.

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.

Key Words: Dishevelled • Notch • Wnt • Signalling crosstalk • Xenopus

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