Wnt/Wingless Signaling Requires BCL9/Legless-Mediated Recruitment of Pygopus to the Nuclear β-Catenin-TCF Complex

Abstract

Wnt/Wingless signaling controls many fundamental processes during animal development. Wnt transduction is mediated by the association of beta-catenin with nuclear TCF DNA binding factors. Here we report the identification of two segment polarity genes in Drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for Wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human BCL9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking Pygo to beta-catenin. Our results suggest that the recruitment of Pygo permits beta-catenin to transcriptionally activate Wnt target genes and raise the possibility that a deregulation of these events may play a causal role in the development of B cell malignancies.

Wnt signaling in disease and in development

“…Further interactions between the β-catenin-TCF complex and chromatin could be mediated by Legless (Bcl9) and Pygopos [29][30][31]. Mutations in either of these genes result in wingless-like phenotypes in Drosophila, and both genes promote Wnt signaling in mammalian cell culture experiments [30].…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…It was identified through its association with BCL9/Legless, which binds to b-catenin ( Fig. 2A; Kramps et al 2002;Thompson et al 2002;Hoffmans and Basler 2004;Townsley et al 2004;Li et al 2007). That said, Pygo can also directly interact with TCFs in a Wnt-independent manner, where it appears to serve as a histone methylation reader and context-dependent LEF/ TCF anti-repressor to facilitate subsequent Wnt-dependent transcription (de la Roche and Bienz 2007;Mieszczanek et al 2008;Gu et al 2013).…”

“…Also participatory in this chromatin activation step is the H3K79 methyltransferase Dot1l, which, in the intestinal crypt, has been shown to be recruited to Wnt target genes in a b-catenin-dependent manner, thereby orchestrating broader chromatin remodeling and transcriptional elongation (Mahmoudi et al 2010). Recruitment of BCL9 and Pygo are known to enhance b-catenin transactivator activity, although the mechanisms are still unfolding (Kramps et al 2002;Thompson et al 2002;Hoffmans and Basler 2004;Townsley et al 2004;Li et al 2007). Conversely, when nuclear b-catenin is absent, TCF3 and/or TCF4 proteins interact with transcriptional repressor Groucho/TLEs and in turn recruit histone deacetylase (HDAC) to yield an inactive chromatin state for the target genes.…”

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

“…BCL9-Like ( BCL9L , also known as B9L or BCL9-2 ) and BCL9 are vertebrate orthologs of Drosophila legless 21 -24 , an essential component of Wnt / Wingless signalling in fl ies. Legless functions as an adaptor linking Armadillo ( Drosophila β -catenin) and Pygopus (Pygo), a transcriptional co-activator 21 .…”