Erect Wing facilitates context-dependent Wnt/Wingless signaling by recruiting the cell-specific Armadillo-TCF adaptor Earthbound to chromatin

Abstract

SUMMARYDuring metazoan development, the Wnt/Wingless signal transduction pathway is activated repetitively to direct cell proliferation, fate specification, differentiation and apoptosis. Distinct outcomes are elicited by Wnt stimulation in different cellular contexts; however, mechanisms that confer context specificity to Wnt signaling responses remain largely unknown. Starting with an unbiased forward genetic screen in Drosophila, we recently uncovered a novel mechanism by which the cell-specific co-factor Earthbound 1 (Ebd1), and its human homolog jerky, promote interaction between the Wnt pathway transcriptional co-activators -catenin/Armadillo and TCF to facilitate context-dependent Wnt signaling responses. Here, through the same genetic screen, we find an unanticipated requirement for Erect Wing (Ewg), the fly homolog of the human sequence-specific DNA-binding transcriptional activator nuclear respiratory factor 1 (NRF1), in promoting contextual regulation of Wingless signaling. Ewg and Ebd1 functionally interact with the Armadillo-TCF complex and mediate the same context-dependent Wingless signaling responses. In addition, Ewg and Ebd1 have similar cell-specific expression profiles, bind to each other directly and also associate with chromatin at shared genomic sites. Furthermore, recruitment of Ebd1 to chromatin is abolished in the absence of Ewg. Our findings provide in vivo evidence that recruitment of a cell-specific co-factor complex to specific chromatin sites, coupled with its ability to facilitate Armadillo-TCF interaction and transcriptional activity, promotes contextual regulation of Wnt/Wingless signaling responses.

Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing

“…We further find that Ebd is also required for the autonomous hyperactivation of Wingless signaling in ISCs that results in their overproliferation following Apc1 loss. This novel finding reveals that Ebd is required for Wnt signaling during both normal homeostasis of the intestine and its aberrant hyperplasia, in addition to Ebd’s previously documented roles in muscles and neurons [53,54]. Similar to that in other tissues, the role of Ebd in the intestine is context-specific, as not all Wnt-mediated processes are dependent on Ebd; Ebd promotes the Wnt-mediated regulation of ISC proliferation during homeostasis, but is dispensable for the Wnt-dependent specification of cell fate near intestinal compartment boundaries [92].…”

Homothorax and Extradenticle alter the transcription factor network in Drosophila ommatidia at the dorsal rim of the retina

“…Interestingly, high levels of ara had a perturbing effect on both induced and endogenous DRA, as Hth/Exd failed to efficiently repress Sens. These results further highlight the importance of finely tuned signals in the dorsal periphery of the retina for correctly specifying cell fates (Tomlinson, 2003;Wernet et al, 2003;Xin et al, 2011). Interestingly, Wg/Wnt signaling is also required for dorsal retinal identity in vertebrates (Veien et al, 2008), and the T-box transcription factors Tbx2, Tbx3 and Tbx5, orthologs of Omb, also play an important role in retinal differentiation along the dorsoventral axis (Wong et al, 2002;Gross and Dowling, 2005; Behesti et al, 2006).…”

“…During pupal stages, Hth becomes specifically expressed in both R7 and R8 of DRA ommatidia, and it is never found in photoreceptors outside the DRA. Expression of Hth at the dorsal eye margin is induced by the Wingless (Wg) signaling pathway (Tomlinson, 2003;Wernet et al, 2003;Xin et al, 2011). Wg signaling is active at both eye margins, and Iro-C provides dorsal-specific identity (Cavodeassi et al, 1999; Cavodeassi et al, 2000).…”

Drosophila Erect wing (Ewg) controls mitochondrial fusion during muscle growth and maintenance by regulation of the Opa1-like gene

“…However, there are no reports linking Ewg with mitochondrial biology. It is known that Ewg is expressed widely, including in developing neurons (DeSimone and White, 1993), larval salivary glands (Xin et al, 2011), larval fat bodies (Baltzer et al, 2009) and pupal indirect flight muscles (IFMs) (DeSimone and White, 1993). The function of Ewg in larval salivary glands and fat body is not known.…”