Developmental phenotypes and reduced Wnt signaling in mice deficient for pygopus 2

Abstract

Canonical Wnt signaling involves complex intracellular events culminating in the stabilization of beta-catenin, which enters the nucleus and binds to LEF/TCF transcription factors to stimulate gene expression. Pygopus was identified as a genetic modifier of Wg (Wnt homolog) signaling in Drosophila, and encodes a PHD domain protein that associates with the beta-catenin/LEF/TCF complex. Two murine pygopus paralogs, mpygo1 and mpygo2, have been identified, but their roles in development and Wnt signaling remain elusive. In this study, we report that ablation of mpygo2 expression in mice causes defects in morphogenesis of both ectodermally and endodermally derived tissues, including brain, eyes, hair follicles, and lung. However, no gross abnormality was observed in embryonic intestine. Using a BAT-gal reporter, we found Wnt signaling at most body sites to be reduced in the absence of mpygo2. Taken together, our studies show for the first time that mpygo2 deletion affects embryonic development of some but not all Wnt-requiring tissues.

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.…”

Wnt Signaling from Development to Disease: Insights from Model Systems

“…However, even though Pygo's biochemical properties are conserved in mammalian Pygo1 and Pygo2 (Fiedler et al 2008;Kramps et al 2002), pygo1, pygo2 or double knockouts in mice have a surprisingly mild decrease in Wnt signaling (Li et al 2007a;Schwab et al 2007;Song et al 2007). Perhaps this is because mouse BCL9 contains its own transactivation domain (Sustmann et al 2008).…”

A role of Pygopus as an anti-repressor in facilitating Wnt-dependent transcription

“…In doing so, it may predispose these genes for Wingless-induced transcription, or oppose their terminal shut-down by transcriptional repressors after a Wingless signaling phase. Importantly, the observed bypass of Pygo function in Drosophila gro mutants could provide an explanation why Pygo proteins appear less critical for Wnt outputs in vertebrates compared with the fly (27)(28)(29)(30)(31): it is conceivable that vertebrate Wnt target genes are naturally derepressed and/or poised for transcriptional activity, so their Wnt inducibility depends to a lesser extent on the anti-repressor function of Pygo than in flies.…”

“…Vertebrates encode two Pygo orthologues, which contribute to efficient ␤-catenin-mediated transcription during development (27)(28)(29)(30)(31) and in cancer cell lines with high Wnt pathway activity (24,32), although their roles in Wnt signaling seem to be less critical than in flies. Pygo proteins are nuclear proteins that associate with Armadillo/␤-catenin via the adapter protein Legless (or BCL9), although their molecular function with regard to TCF-dependent transcription remains unclear.…”