Erect Wing facilitates context-dependent Wnt/Wingless signaling by recruiting the cell-specific Armadillo-TCF adaptor Earthbound to chromatin.
During 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 β-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.
Department of Genetics and Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
Nan
N
Xin
Hassina
H
Benchabane
Ai
A
Tian
Kerrie
K
Nguyen
Lindsay
L
Klofas
Yashi
Y
Ahmed
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051936:Centromere Protein B / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004330:Drosophila / Q000196:embryology / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004625:Embryo, Nonmammalian; D057809:HEK293 Cells; D006801:Humans; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C495305:ARM protein, Drosophila; D048868:Adaptor Proteins, Signal Transducing; D051186:Armadillo Domain Proteins; D051936:Centromere Protein B; D002843:Chromatin; D029721:Drosophila Proteins; C081334:EWG protein, Drosophila; C559018:Ebd1 protein, Drosophila; D009479:Neuropeptides; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051155:Wnt1 Protein; C074622:wg protein, Drosophila