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. 2008 Aug;15(2):309-21.
doi: 10.1016/j.devcel.2008.06.003.

Morphogen control of wing growth through the Fat signaling pathway

Dragana Rogulja  1 , Cordelia Rauskolb, Kenneth D Irvine
Affiliations

Morphogen control of wing growth through the Fat signaling pathway

Dragana Rogulja et al. Dev Cell. 2008 Aug.

Abstract

Organ growth is influenced by organ patterning, but the molecular mechanisms that link patterning to growth have remained unclear. We show that the Dpp morphogen gradient in the Drosophila wing influences growth by modulating the activity of the Fat signaling pathway. Dpp signaling regulates the expression and localization of Fat pathway components, and Fat signaling through Dachs is required for the effect of the Dpp gradient on cell proliferation. Juxtaposition of cells that express different levels of the Fat pathway regulators four-jointed and dachsous stimulates expression of Fat/Hippo pathway target genes and cell proliferation, consistent with the hypothesis that the graded expression of these genes contributes to wing growth. Moreover, uniform expression of four-jointed and dachsous in the wing inhibits cell proliferation. These observations identify Fat as a signaling pathway that links the morphogen-mediated establishment of gradients of positional values across developing organs to the regulation of organ growth.

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Figures

Figure 1
Figure 1. Polarization of Dachs localization in the wing
A) Schematic of a portion the wing imaginal disc. The approximate location of Wg-expressing cells along the D–V boundary (red) and Dpp-expressing cells along the A–P boundary (yellow) are shown. The region illustrated here as distal (green) corresponds to Vestigial-expressing cells, which give rise to the wing blade. B–D) Show portions of wing imaginal discs with clones of cells expressing Dachs:V5 (red). B) In a clone of cells mutant for fat8 and expressing Dachs:V5, Dachs is on the membrane all around the clone circumference. C,D) Two examples of wild-type discs with many small Dachs:V5-expressing clones, the D–V boundary and wing pouch are demarcated by wg-lacZ[ro216] expression (green). Arrows indicate the vectors of Dachs polarization for selected clones. Panels -1 and -2 show close-ups of the boxed regions; box 1 shows clones near the D–V boundary but far from the A–P boundary and box 2 shows clones near the A–P boundary but far from the D–V boundary.
Figure 2
Figure 2. Dpp signaling influences Fat signaling components
A,B,E,F) Show wing imaginal discs containing tub-Gal4/Gal80ts clones, 24–28h after temperature shift-mediated induction of expression, G) shows a disc with a Gal4:PR-expressing clones at 18 h after RU486-mediated induction of expression; all clones were marked by expression of GFP (green). In this and subsequent figures, panels marked prime show a single channel of the image to the left. A) Clones expressing Dachs:V5 and TKVQ-D. Dachs is not on the membrane on the distal side of the clone (arrow). A’ shows a close-up of the boxed area in A. B) Clones expressing Dachs:V5 and Brinker. B’ shows a close-up of the boxed area in B. Dachs is on the membrane on all sides of the clone, arrowhead points to proximal edge. C) fj expression (fj-lacZ) is highest in distal wing cells, and modestly graded from distal to proximal. D) ds expression (ds-lacZ) is highest in proximal wing cells, and modestly graded from proximal to distal. E) fj-lacZ expression is upregulated within clones expressing TKVQ-D (arrow). F) ds-lacZ expression is repressed in the proximal wing within clones expressing TKVQ-D (arrow). G) Ds protein is relocalized around the edges of clones expressing TkvQ-D and appears diminished within the clone. G’ shows a close-up of the boxed area in G.
Figure 3
Figure 3. Dpp signaling influences Fat/Hippo pathway target genes
Wing imaginal discs, stained for expression of Diap1 (A, C, D, F–H) or ex-lacZ (B, E) (red). C–H) contain tub-Gal4/Gal80ts clones marked by co-expression of GFP. Arrows point to examples of Fat/Hippo target gene upregulation around clone edges. A,B) Wild-type discs. C) TkvQ-D– expressing clone. Strong Diap1 upregulation is observed in lateral regions, but the effect is subtle in the medial wing, where endogenous Tkv activity is high. D) Close-up of a TkvQ-D-expressing clone, Diap1 upregulation is strongest in cells immediately neighboring the clone, but examples of upregulation two to three cells away (arrow) and inside the clone border (arrowhead) can be observed. E) TkvQ-D–expressing clone, ex-lacZ is upregulated around clone edges, except near the D–V boundary. F) Brinker-expressing clone. Diap1 is downregulated inside the clone, but upregulated just outside, mimicking the effects of Brinker on BrdU labeling (Rogulja and Irvine, 2005). G) Clones in which Tkv levels have been downregulated by RNAi. Diap1 upregulation is observed along clone edges. H) Close-up of a clone in G.
Figure 4
Figure 4. dachs is required for non-autonomous influences of Tkv on cell proliferation
A–D Show wing imaginal discs containing Gal4:PR-expressing clones, marked by expression of GFP (green), grown for 15 hours on media containing RU486 and then labeled and stained for BrdU (red), or phospho-Mad (magenta). For ease of comparison, the locations of selected clones are outlined by dashes. Because the nuclei are not all in the same focal plane, we combined staining in different focal planes by maximum projection through confocal sections. A) AyGal4:PR UAS-1tkvQ253D UAS-GFP. BrdU labeling is elevated around the clone. B) AyGal4:PR UAS-GFP. BrdU labeling is normal C) dachsGC13; AyGal4:PR UAS-TkvQ253D UAS-GFP. BrdU labeling is autonomously elevated within a lateral clone (asterisk), but no non-autonomous elevation of labeling is observed. D) dachsGC13; AyGal4:PR UAS-TkvQ253D UAS-GFP, p-MAD staining is elevated in TKVQ-D-expressing clones. E–F Show discs with uniform TkvQ253D expression, induced by actin-Gal4:PR. E) In wild type this represses BrdU labeling in medial cells (asterisk)(Rogulja and Irvine, 2005), but F) in fat no medial repression occurs. G) dachs mutant wing imaginal discs containing tub-Gal4/Gal80ts clones expressing TkvQ253D, stained for expression of Diap1 (red). Diap1 expression is not affected by the clones. H) Close-up of a clone shown in G.
Figure 5
Figure 5. Fj- or Ds-expressing clones elevate BrdU incorporation
A–F show wing imaginal discs containing Gal4:PR-expressing clones, marked by expression of GFP (green), grown for the indicated number of hours on media containing RU486, and labeled and stained for BrdU. For ease of comparison, the locations of selected clones are outlined by dashes. A,E) AyGal4:PR UAS-ds UAS-GFP. Elevated BrdU labeling is evident in A, especially in distal regions, but not in E. B,F) AyGal4:PR UAS-fj UAS-GFP. Elevated BrdU labeling is evident, especially in proximal regions. C) dachsGC13; AyGal4:PR UAS-ds UAS-GFP. BrdU labeling is not affected by the clones. D) dachsGC13; AyGal4:PR UAS-fj UAS-GFP. BrdU labeling is not affected by the clones. G) tub-Gal4/Gal80ts clones expressing ds; Diap1 staining is elevated around the clones (arrows). H) dachsGC13 mutant with tub-Gal4/Gal80ts clones expressing ds, Diap1 staining is not affected by the clones.
Figure 6
Figure 6. Uniform Fj and Ds expression inhibits BrdU incorporation & wing growth
Panels A–F show discs grown for the indicated number of hours on media containing RU486 and then labeled and stained for BrdU (red). A) UAS-ds UAS-fj actin>Gal4:PR UAS-GFP. B) UAS-ds actin>Gal4:PR UAS-GFP. C) UAS-fj actin>Gal4:PR UAS-GFP. D–F) UAS-ds UAS-fj actin>Gal4:PR UAS-GFP. G–J show adult wings, all at the same magnification, from animals with a tub-Gal4 transgene and G) No UAS transgene H) UAS-ds, I) UAS-fj, J) UAS-ds UAS-fj. K) Histogram of the average areas of ten female wings of the genotypes in G–J, normalized to the average area in wild-type. Error bars indicate one standard deviation.
Figure 7
Figure 7. Model for regulation of Fat signaling by a Dachsous gradient
A) Schematic of a cell within a Ds gradient. Characterization of Fat staining in discs with clones of cells mutant for or over-expressing Ds indicates that localization of Fat at the membrane can be influenced by the levels of Ds in neighboring cells. Since every cell in a Ds gradient sees more Ds on one side than it does on the other, we suggest that Fat protein could be asymmetrically localized (as indicated). Alternatively, Fat might be uniformly localized but asymmetrically activated. If this asymmetric localization or activity influenced Fat and Ds in neighboring cells, then the asymmetry could be propagated through local cell-cell interactions. The asymmetric localization and/or activity of Fat within a cell results in asymmetric localization of Dachs to the membrane (Fig. 1)(Mao et al., 2006). We suggest that where Dachs can accumulate at the membrane, it locally promotes the degradation and inactivation of Warts (Cho et al., 2006; Feng and Irvine, 2007). We further suggest that Warts locally inhibits the activity of its substrate, Yki (Huang et al., 2005), but where Warts is absent active Yki can be produced, which would then enter the nucleus (arrow) and regulate gene expression to promote growth (Dong et al., 2007; Oh and Irvine, 2008). A transcriptional signal in this context is thus generated from a side of cell opposite to where Fat and Ds are engaged. B) When Ds is uniformly expressed, active Fat would be localized to the membrane around the entire circumference of the cell, where it would antagonize the localization of Dachs to the membrane (Mao et al., 2006). This in turn would allow accumulation of active Warts, and consequently increase inhibition of Yki. C) In the absence of Ds or Fat, Dachs would accumulate at the membrane around the entire circumference of the cell, resulting in uniformly low levels of active Warts, and thereby allowing more Yki to enter the nucleus. By modulating Fat-Ds interactions, a gradient of Four-jointed (not shown) could establish a gradient of Ds-Fat binding activity even under conditions where Ds expression is relatively uniform.
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