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Development December 1, 2012; 139 (23): 4405-15.

Dishevelled limits Notch signalling through inhibition of CSL.

Collu GM , Hidalgo-Sastre A , Acar A , Bayston L , Gildea C , Leverentz MK , Mills CG , Owens TW , Meurette O , Dorey K , Brennan K .

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.

PubMed ID: 23132247
PMC ID: PMC3509734
Article link: Development
Grant support: [+]

Species referenced: Xenopus
Genes referenced: ank1 dvl2 gal.2 gnl3 hes5.1 jpt1 mn1 myc notch1 notch4 notch4.2 prl.2 rbpj rpl8 smpx
Morpholinos: dvl2 MO3

Article Images: [+] show captions
References [+] :
Amoyel, Wnt1 regulates neurogenesis and mediates lateral inhibition of boundary cell specification in the zebrafish hindbrain. 2005, Pubmed