How targets select activation or repression in response to Wnt

Abstract

In metazoans, the Wnt signaling pathway plays a key role in the regulation of binary decisions during development. During this process different sets of target genes are activated in cells where the Wnt pathway is active (classic target genes) versus cells where the pathway is inactive (opposite target genes). While the mechanism of transcriptional activation is well understood for classic target genes, how opposite target genes are activated in the absence of Wnt remains poorly characterized. Here we discuss how the key transcriptional mediator of the Wnt pathway, the TCF family member POP-1, regulates opposite target genes during C. elegans development. We examine recent findings suggesting that the direction of the transcriptional output (activation or repression) can be determined by the way TCF is recruited and physically interacts with its target gene.

pop-1/TCF, ref-2/ZIC and T-box factors regulate the development of anterior cells in the C. elegans embryo

“…This difference in the regulatory activity of TCF is mediated by an allosteric conformational change in the structure of TCF [22]. In C. elegans, POP-1 bound together with REF-2 at the ttx-3 cis-regulatory region, may similarly undergo allosteric changes, leading to opposite target regulation [20,21]. Our findings are consistent with a similar mechanism regulating ref-2 itself.…”

“…Furthermore, POP-1 and REF-2 can directly interact, suggesting that REF-2 and POP-1 bind as a complex to activate ttx-3 expression in the AIY mother. The role of SYS-1 is less clear but some evidence suggests SYS-1 may bind to the POP-1/REF-2 complex to repress expression, or may sequester away the limited POP-1, such that POP-1 cannot interact with 21]. Similar regulation, termed "opposite Wnt regulation", has also been seen in other organisms such as Drosophila [22].Because of the role of POP-1 and SYS-1 in regulating the anterior-specific expression of ttx-3, we hypothesized that these genes may also regulate other anterior genes.…”

β‐catenin‐driven binary cell fate decisions in animal development

“…18,59,61 While the mechanism of transcriptional activation of posterior target genes in posterior daughters is well studied, the mechanism whereby anterior target genes are specifically activated in anterior daughters is less well understood. 64 One simple mechanism could be that the POP-1:SYS-1 complex directly activates the expression of a transcriptional repressor in the posterior daughter; this repressor then represses the expression of anterior targets in the posterior daughter, therefore restricting their expression to the anterior daughter (Figure 7(b)). There is indeed evidence for such a mechanism in some lineages.…”

Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development

“…The binding of POP-1 with the WRM-1/LIT-1 complex and the binding of POP-1 to its transcriptional coactivator SYS-1 (discussed further in the chapter) use distinct binding domains but are mutually exclusive (Yang et al, 2011). Though recent evidence demonstrates that POP-1 can interact with other DNA binding factors to activate transcription in a WβA-independent manner(Murgan and Bertrand, 2015, Murgan et al, 2015), the above data show that POP-1 contains distinct domains that bind to either its activator SYS-1 or the effector of its export, WRM-1, to control its transcriptional activity and subsequently the expression of WβA target genes.…”

“…These include the β-catenin dependent or “canonical” Wnt signaling pathway, the Wnt planar cell polarity (PCP) pathway, and the Ca 2+ /Calmodulin pathway (Sokol, 2015, Gao and Chen, 2010). Though Wnt/PCP is often associated with polarizing cells in various contexts including vertebrate convergent extension and the fly eye and wing bristle (Axelrod et al, 1996, Wehrli and Tomlinson, 1998, Klein and Mlodzik, 2005, Gao, 2012) and the Wnt/Ca2+ pathway also polarizes cell movements during gastrulation (Lin et al, 2010), the Wnt/β-catenin canonical pathway regulates mother cell polarity at the time of division and subsequent asymmetry of newly-formed daughter cells in addition to its a well-established role in transcriptional activation, cell proliferation, differentiation and stem cell maintenance (Habib et al, 2013, Sawa and Korswagen, 2013, Murgan and Bertrand, 2015, Munro and Bowerman, 2009, Hardin and King, 2008). …”