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. 2008 Jul 15;105(28):9645-50.
doi: 10.1073/pnas.0803747105. Epub 2008 Jul 9.

The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like

Luis Alberto Baena-Lopez  1 , Isabel Rodríguez, Antonio Baonza
Affiliations

The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like

Luis Alberto Baena-Lopez et al. Proc Natl Acad Sci U S A. .

Abstract

The activity of different signaling pathways must be precisely regulated during development to define the final size and pattern of an organ. The Drosophila tumor suppressor genes dachsous (ds) and fat (ft) modulate organ size and pattern formation during imaginal disc development. Recent studies have proposed that Fat acts through the conserved Hippo signaling pathway to repress the expression of cycE, bantam, and diap-1. However, the combined ectopic expression of all of these target genes does not account for the hyperplasic phenotypes and patterning defects displayed by Hippo pathway mutants. Here, we identify the glypicans dally and dally-like as two target genes for both ft and ds acting via the Hippo pathway. Dally and Dally-like modulate organ growth and patterning by regulating the diffusion and efficiency of signaling of several morphogens such as Decapentaplegic, Hedgehog, and Wingless. Our findings therefore provide significant insights into the mechanisms by which mutations in the Hippo pathway genes can simultaneously alter the activity of several signaling pathways, compromising the control of growth and pattern formation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Ds modulates the activity of different signaling pathways. (A–F) Third-instar wing discs containing clones of a null allele of ds (dsD36). Mutant cells are marked by the absence of GFP (in green). (A and B) Whereas some dsD36 cells can express pMad (in red) beyond its normal domain of expression (red arrowheads in A and A′), other cells show a reduction in pMad levels (yellow arrowheads in A and A′). dsD36 clones located in the lateralmost part of the disc do not up-regulate pMad (asterisk). (B and B′) Two different optical Z sections shown in A (L1 and L2) illustrate the distribution of pMad. This protein is nonautonomous up-regulated in some of the surrounding wild-type cells (red arrowheads in B and B′). (C and D) The expression of Ptc (in red) and (E and F) Vg (in red) is reduced in dsD36 cells (red arrowheads). (D and F) Ptc and Vg expression, respectively, Z sections along A/P axis in dsD36 clones. Gray, expression of pMad (A′ and B′), Ptc (C′ and D′), and Vg (E′ and F′).
Fig. 2.
Fig. 2.
dally and dlp are transcriptionally up-regulated in ds mutant cells. (A–C) Third-instar imaginal wing discs containing dsD36 mutant clones. (D and E) Third-instar wing discs expressing dpp-Gal4/UAS-yki. (A and A′) dsD36 cells, marked by the absence of GFP (in green) express high levels of Dlp protein (red) (yellow arrowheads) and (B and B′) dallyZ in a cell-autonomous manner. Optical Z-sections from A and B are shown. White bar indicates the position of the section. (C and C′) The levels of dlp mRNA (blue) are increased in dsD36 cells, marked by the absence of β-galactosidase staining (brown). (C′) High magnification of a clone (outlined in white) shown in C. (D and D′) Third-instar wing discs expressing dpp-Gal4/UAS-yki show up-regulation of Dlp protein (in red) and (E and E′) dlp mRNA (blue). Gray, expression of Dlp protein (A′ and D′) and dallyZ (B′).
Fig. 3.
Fig. 3.
Activation of the Hippo pathway causes down-regulation of Dlp. (A and A′) In third-instar sal-Gal4/UAS-P35; UAS-HpoWT wing discs, the expression of Dlp (green) is reduced within the sal-Gal4 domain (marked in red with anti-P35). Z sections are shown to visualize Dlp levels (in green). White bars indicate the position of the section. Nuclei were monitored with Tropo staining (blue). (B and B′) In ftG−rv clones, positively marked with GFP (green), the levels of expression of Dlp (red) (yellow arrowhead) are higher than in the wild-type surrounding cells. (C and C′) Ectopic expression of UAS-HpoWt in ftG-rv cells (green) prevents the accumulation of high levels of Dlp (red).
Fig. 4.
Fig. 4.
Ectopic expression of yki mimics the signaling defects caused by overexpression of dally and dlp. (A–E) Analysis of pMad and Ptc expression in third-instar wing discs of the following genotypes: ap-Gal4/UAS-dally; UAS-dlp (A–A″), ap-Gal4/UAS-yki (B–B″), and discs containing cell-expressing clones of UAS-yki (C–C″), UAS-yki; FRT2A dally80 dlpA187 (UAS-yki dally−dlp−) (D–D″), and FRT2A dally80 dlpA187 (E–E″). In all wing discs, the cells overexpressing different transgenes were marked with GFP in green and stained with anti-pMad (red) and anti-Ptc (blue). (A) Co-overexpression of UAS-dally; UAS-dlp produces a combination of phenotype; close to the D/V border the expression of pMad is expanded (yellow arrow in A′), whereas in other dorsal regions pMad is down-regulated (arrowhead in A′). (A″) In dorsal cells, the stripe of Ptc expression seems thinner (yellow arrowhead) than in ventral cells (yellow arrow). (B and B′) In ap-Gal4/UAS-yki wing discs, pMad expression is expanded in some dorsal cells (yellow arrow), whereas it is down-regulated in other dorsal cells (yellow arrowhead). (B″) In dorsal cells, the stripe of Ptc seems thinner (yellow arrow). Below each panel, two optical Z sections (from ventral and dorsal compartments, respectively) illustrate the distribution of pMad and Ptc along A/P axis. Z sections were aligned with respect to Ptc expression. (C and C′) Some clones of yki-expressing cells express pMad outside the normal pMad expression domain (yellow arrowheads in C′), whereas other clones display reduced pMad levels (yellow arrow in C′). (C″) The levels of Ptc are down-regulated in some of these clones (yellow arrow). (D and D′) Clones of UAS-yki; dally−dlp− cells are unable to up-regulate pMad (arrowhead in D and arrows in D′). In these clones the defect in Ptc expression caused by ectopic yki expression is restored. Occasionally, we find a slight down-regulation of Ptc (arrow in D″). (E and E′) In dally−dlp− clones we always observed a reduction of the levels of pMad (red) (arrows in E′) and a slight reduction in Ptc expression (arrow in E″). Clones were induced at 84 ± 12 h after egg laying (AEL) and analyzed 72 h after induction except in E, where they were induced at 60 ± 12 h AEL. Two optical Z sections at different positions within the wing disc (yellow and blue lines) are shown. These sections were aligned with respect to Ptc expression.
Fig. 5.
Fig. 5.
dlp and dally contribute to the overgrowth phenotypes displayed by ft mutants and the ectopic expression of yki. (A) The size of ft18/ftG-rv; dally80 dlpA187/dallyP1 wing discs is much smaller than of ft18/ftG-rv discs. Third-instar wing discs were stained with Ptc antibody. (B) Similarly, adult pharates from ft18/ftG-rv; dally80 dlpA187/dallyP1 flies show a suppression of the overgrowth phenotype compared with ft18/ftG-rv flies. Moreover, ft18/ftG-rv; dally80 dlpA187/dallyP1 flies display everted wings, and the notum size is similar to wild type. Magnification is the same in all panels. (C) Quantitative analysis of the clone sizes in the different genetic backgrounds. Clones were induced at 72–96 h AEL and analyzed 72 h later (n = 43).
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References

    1. Clark HF, et al. Dachsous encodes a member of the cadherin superfamily that controls imaginal disc morphogenesis in Drosophila. Genes Dev. 1995;9:1530–1542. - PubMed
    1. Saburi S, McNeill H. Organising cells into tissues: New roles for cell adhesion molecules in planar cell polarity. Curr Opin Cell Biol. 2005;5:482–488. - PubMed
    1. Baena-López LA, Baonza A, García-Bellido A. The orientation of cell divisions determines the shape of Drosophila organs. Curr Biol. 2005;15:1640–1644. - PubMed
    1. Rodríguez I. The dachsous gene, a member of the cadherin family, is required for Wg-dependent pattern formation in the Drosophila wing disc. Development. 2004;131:3195–3206. - PubMed
    1. Tyler DM, Baker NE. Expanded and Fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol. 2007;305:187–201. - PMC - PubMed

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