Abstract
The atypical cadherins Fat (Ft) and Dachsous (Ds) control tissue growth through the Salvador–Warts–Hippo (SWH) pathway, and also regulate planar cell polarity and morphogenesis. Ft and Ds engage in reciprocal signalling as both proteins can serve as receptor and ligand for each other. The intracellular domains (ICDs) of Ft and Ds regulate the activity of the key SWH pathway transcriptional co-activator protein Yorkie (Yki). Signalling from the FtICD is well characterized and controls tissue growth by regulating the abundance of the Yki-repressive kinase Warts (Wts). Here we identify two regulators of the Drosophila melanogaster SWH pathway that function downstream of the DsICD: the WD40 repeat protein Riquiqui (Riq) and the DYRK-family kinase Minibrain (Mnb). Ds physically interacts with Riq, which binds to both Mnb and Wts. Riq and Mnb promote Yki-dependent tissue growth by stimulating phosphorylation-dependent inhibition of Wts. Thus, we describe a previously unknown branch of the SWH pathway that controls tissue growth downstream of Ds.
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Acknowledgements
We thank C. House for assistance with mass spectrometry, J. Lin and K. Hannan for expertise with kinase assays and S. Blair (University of Madison, Wisconsin, USA), I. Edery (Rutgers University, USA), C. House (Peter MacCallum Cancer Centre, Australia), K. Irvine (Rutgers University, USA), D. Pan (Johns Hopkins University, USA), M. Simon (Stanford University, USA), D. Strutt, University of Sheffield, UK), N. Tapon (Cancer Research UK, UK), F. Tejedor (Universidad Miguel Hernandez, Spain), K. Yu (Korea Research Institute of Bioscience and Biotechnology), the Developmental Studies Hybridoma Bank, the Vienna Drosophila RNAi Center, the Australian Drosophila Research Support Facility (www.ozdros.com), the National Institute of Genetics and the Bloomington Stock Centre for fly stocks, plasmids and antibodies. K.F.H. is a Sylvia and Charles Viertel Senior Medical Research Fellow. This research was supported by a Project Grant from the National Health and Medical Research Council of Australia, and by NIH grants GM097727 and CA156734 and NSF grant 0640700 to A.V. Mass spectrometry was performed at the Taplin Facility, Harvard Medical School, USA and Bio21, University of Melbourne, Australia.
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J.L.D. and C.C.M. performed Drosophila genetic experiments. J.L.D. and E.Y. carried out biochemistry and molecular biology experiments. M.T., L.Y. and A.V. performed affinity purification and mass spectrometry. F.B. and Y.B. analysed Dachs localization in the pupal notum. J.L.D. and K.F.H. designed experiments, analysed data and wrote the manuscript.
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Integrated supplementary information
Supplementary Figure 1 Dachsous promotes localization of Riquiqui to apical junctions and cell membranes.
(a-c”) X-Z cross-sections of D. melanogaster third instar larval wing imaginal discs expressing the following elements: (a, a’, a”) rn-Gal4, UAS-riq; (b, b’, b”) rn-Gal4, UAS-riq and UAS-ds; (c, c’, c”) rn-Gal4, UAS-riq and UAS-dsRi. Riq is in white, E-cadherin marks the adherens junction in green. Arrows indicate Riq protein that is present at apical junctions in Ds-expressing tissues. Magnified images are inset in (a) (a’) (b) and (b’). Merged images are on the right. Riq was junctionally localised immediately apical to E cadherin. Riq was largely absent from apical junctions of tissues where Ds was depleted by RNAi. (d and e) D. melanogaster S2 cells expressing either Riq (d) or Riq and DsΔECD (e). Riq is in red, DsΔECD is green, Direct interference contrast (DIC) images are grey. Arrows indicate Riq protein that is present at cell membranes in DsΔECD-expressing cells. Scale bar represents 10 μm in (a-c”) and 5 μm in (d) and (e).
Supplementary Figure 2 UAS-riq RNAi transgenes decrease Riq expression.
(a) A wing imaginal disc from a third instar D. melanogaster larva expressing UAS-riqi1 under the control of hh-Gal4. Riq expression (grey in a) was assessed using an antibody directed against DCAF7 (human homologue of Riq). Cubitus interruptus (Ci) expression (red in a’) marked the anterior compartment of wing imaginal discs. A merged image is shown in (a”). (b) The level of riq mRNA relative to the control actin5C mRNA, assessed by QRT-PCR, in wing imaginal discs harbouring the following transgenes: hh-Gal4 and UAS-EYFP; or hh-Gal4 and UAS-riqi1. Data is presented as mean±SEM,n = 3, ** = p<0.01. Scale bar represents 50 μm in (a). Statistics source data for Supplementary Fig. S2b is available in Supplementary Table S1.
Supplementary Figure 3 Riquiqui and Minibrain regulate SWH pathway activity.
Wing imaginal discs from third instar D. melanogaster larvae harbouring the following elements: (a-a”) en-Gal4, UAS-EYFP and th-lacZ; (b-b”) en-Gal4, UAS-riq and th-lacZ; (c-c”) en-Gal4, UAS-mnb and th-lacZ; (d,d’) hh-Gal4, UAS-EYFP and ex-lacZ; (e,e’) hh-Gal4, UAS-riq and ex-lacZ; (f,f’) hh-Gal4, UAS-mnb and ex-lacZ; (g,g’) hh-Gal4, UAS-riq, UAS-mnb and ex-lacZ. Yki activity (grey) was reported by th-lacZ (a–c) or ex-lacZ (d–g). All transgenes were expressed in the posterior compartment of wing imaginal discs; Ci expression (red) marks the anterior compartment. Merged images are shown in (a”–c” and in d’–g’). (h) An adult female fly expressing both riq and mnb under control of the rn-Gal4 driver. Unlike driving expression of riq and mnb alone, driving expression of both transgenes together caused severe folding and crumpling of wings, which prevented quantification of their size. (e) Quantification of LacZ expression driven by ex-lacZ, ban-lacZ or th-lacZ in wing imaginal discs displayed in Fig. 3 and Supplementary Fig. S3a–c. Anterior is to the left. For each disc fluorescence intensity was measured by ImageJ in two boxes of defined size in both the anterior (ant.) and posterior (post.) compartments. These values were averaged and plotted for each experiment. Scale bar represents 50 μm.
Supplementary Figure 4 Riquiqui and Minibrain affect wing growth independently of Dachs.
Wing imaginal discs from third instar D. melanogaster larvae containing clones of UAS-riqi1 (a) or UAS-mnbi1 (b) were stained for Dachs (grey in a and b). Clones were positively marked by co-expression of GFP (a’ and b’). Merged images are shown in (a” and b”). X-Z sections through the wing pouch are shown below planar sections of wing discs in a–b”. Dashed lines represent the section used to obtain X-Z images. No changes in Dachs expression or localization were observed. (d–e”) All images were recorded in pupal scutellum tissue (right-sided hemi-scutellum) at 20 hour after pupa formation. Anterior is to the right, the midline is to the top. Yellow circles mark the macrocheatae. Spatial information on the Fj-Ds gradient is shown in c as in ref. 1. Flip out clones of UAS-riqi and UAS-mnbi were generated and marked in red (d” and e” respectively). White boxes are magnified in d’ and e’. Yellow dots mark the mutant cells abutting wt cells (d’ and e’). In these Flip-Out clones no clear reduction of D:GFP levels was observed when compared with the surrounding tissue. There is also no clear repolarization of D:GFP near clone boundaries. (f) Wing area from adult female flies expressing UAS-EYFP as control, UAS-riqi, UAS-dachs RNAi (di), UAS-riqi concomitantly with UAS-di, under the control of rn-Gal4 (n = 20 for each genotype). Representative images of each genotype are shown. Data is presented as mean±SEM, *** = p<0.001. These results suggest Dachs and Riq control tissue growth by acting in parallel. Scale bars represents 50 μm in (a) and (b), 10 μm in (c), (d) and (e), and 200 μm in (f).
Supplementary Figure 5 Riquiqui, Minibrain and Warts physically interact with each other and Minibrain phosphorylates Warts.
(a) S2 cells were transfected with the indicated plasmids and immunoprecipitations performed using anti-HA antibodies. Subsequently, immunoprecipitates and input lysates were subjected to SDS-PAGE and Western blotted to reveal the indicated proteins. (b–d) Western blot analysis of lysates from S2 cells transfected with the indicated plasmids and Western blotted to reveal the indicated proteins. In (b) Riq or Mnb were expressed in S2 cells in the presence or absence of dsRNA specific for Riq or Mnb, respectively. In (c) Mnb did not induce changes in Hpo or Sav mobility. In (d) Mnb, but not Hipk influenced Wts mobility. (e) Kinase assays performed using recombinant GST-Wts1 or GST-CACYBP as substrates and either Mnb or Mnb K386R immunoprecipitated from S2 cells. Immunopurified and recombinant proteins were incubated alone or together in kinase buffer containing γ32P-ATP and subjected to SDS-PAGE (upper panel). Western blotting was used to detect input proteins (lower panels). Mnb phosphorylated GST-Wts1 but not the negative control substrate GST-CACYBP. (f) V5-tagged Wts was expressed in the presence or absence of dsRNA specific for Riq or Mnb in S2 cells. Cells were lysed and lysates were immunoblotted using antibodies to V5 and to Tubulin as a loading control. Wts levels were unchanged when Riq or Mnb were depleted from cells by RNAi.
Supplementary Figure 6 Minibrain phosphorylates six amino acids in the Warts protein, including a DYRK1A consensus site.
(a and b) Wts1 (amino acids 1-318 of Wts) peptides that possessed amino acids that were phosphorylated when incubated with either wild-type Mnb or kinase-dead Mnb (Mnb-KD) immunoprecipitates. Experiments 1 and 2 were performed independently and analyzed by different mass spectrometry facilities. In experiment 1, five Wts amino acids were phosphorylated by wild-type Mnb with high confidence, whereas Mnb-KD induced no observable phosphorylation. In experiment 2, six Wts amino acids were phosphorylated by wild-type Mnb with high confidence, whilst two amino acids were phosphorylated in the presence of Mnb-KD. Amino acids that were phosphorylated by Mnb, but not Mnb-KD, are highlighted; amino acids that were phosphorylated in both independent experiments are red and amino acids that were phosphorylated in only one experiment are blue. (c) A summary of mass spectrometry data outlined in (a) and (b). The amino acid sequence of Wts1 is shown and the degree of conservation with human LATS1, as assessed by CLUSTAL, is indicated below: * indicates perfect conservation, : indicates strongly similar;. indicates weakly similar. As in (a) and (b), amino acids that were phosphorylated in both independent experiments by Mnb, but not Mnb-KD, are highlighted in red and amino acids that were phosphorylated by Mnb in only one experiment are in blue. The Wts sequence that was phosphorylated by Mnb and closely resembles a DYRK1A consensus site (RPXS/TP; ref. 2) is in bold font. Of note, this site was phosphorylated in each experiment and is conserved between Wts and LATS1.
Supplementary Figure 7 Reduction of Riq or Mnb expression does not affect Dachsous expression.
Wing imaginal discs from third instar D. melanogaster larvae containing clones of UAS-riqi1 (a) or UAS-mnbi1 (b) were stained for Ds (grey in a and b). Clones were positively marked by co-expression of GFP (a’ and b’). Merged images are shown in (a” and b”). X-Z sections through the wing pouch are shown below planar sections of wing discs in a–b”. Dashed lines represent the section used to obtain X-Z images. Scale bar represents 50 μm.
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Degoutin, J., Milton, C., Yu, E. et al. Riquiqui and Minibrain are regulators of the Hippo pathway downstream of Dachsous. Nat Cell Biol 15, 1176–1185 (2013). https://doi.org/10.1038/ncb2829
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DOI: https://doi.org/10.1038/ncb2829