Axelrod JD et al. (1998), Differential recruitment of Dishevelled provide...

XB-ART-14392

Genes Dev 1998 Aug 15;1216:2610-22. doi: 10.1101/gad.12.16.2610.

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Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways.

Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N.

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In Drosophila, planar cell polarity (PCP) signaling is mediated by the receptor Frizzled (Fz) and transduced by Dishevelled (Dsh). Wingless (Wg) signaling also requires Dsh and may utilize DFz2 as a receptor. Using a heterologous system, we show that Dsh is recruited selectively to the membrane by Fz but not DFz2, and this recruitment depends on the DEP domain but not the PDZ domain in Dsh. A mutation in the DEP domain impairs both membrane localization and the function of Dsh in PCP signaling, indicating that translocation is important for function. Further genetic and molecular analyses suggest that conserved domains in Dsh function differently during PCP and Wg signaling, and that divergent intracellular pathways are activated. We propose that Dsh has distinct roles in PCP and Wg signaling. The PCP signal may selectively result in focal Fz activation and asymmetric relocalization of Dsh to the membrane, where Dsh effects cytoskeletal reorganization to orient prehair initiation.

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Species referenced: Xenopus
Genes referenced: actl6a dvl1 dvl2

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Figure 1. Dsh–GFP localizes to the membrane and filopodia in response to Fz in Xenopus animal cap cells. (A) Dsh–GFP (green) localizes in the cytoplasm in an apparent association with intracellular vesicles (Texas Red phalloidin labels the cell cortex). (B) In response to Fz, Dsh–GFP redistributes to the plasma membrane. (C) Fz localizes predominantly to the plasma membrane in the presence (shown) or absence (not shown) of Dsh–GFP. (D, D8) Dsh–GFP colocalizes with Fz at the plasma membrane. Yellow staining represents colocalization of Dsh–GFP (green from B) and Fz (red from C) and is marked by an arrow in D8. However, regions of the plasma membrane are also stained only by Dsh–GFP or Fz, demonstrating that the colocalization of Dsh–GFP and Fz is not absolute (arrowheads in D8). (E–G) In response to Fz, Dsh–GFP also accumulates in filopodia that extend from the free surface of the animal cap cells (arrowheads). These filopodia contain actin (stained with phalloidin; arrowhead in G8) but lack Fz (note lack of yellow staining in filopodia in F). (H,I) In contrast to the effects of Fz on the localization of Dsh–GFP, neither DFz2 (H) nor the combination of DFz2 and Wg (I) results in a change in the localization of Dsh–GFP (Dsh–GFP = green). Texas Red phalloidin was used to visualize cell outlines in A, H, and I, and the filopodium in G8.

Figure 2. Analysis of Dsh domains required for Fz-dependent relocalization of Dsh in Xenopus animal cap cells. (A) Dsh(ΔbPDZ)–GFP localizes to the cytoplasm in a punctate pattern. (B) In response to Fz, Dsh(ΔbPDZ)–GFP relocalizes to the plasma membrane (shown) and is also present in filopodia (not shown). (C) Dsh(ΔDIX)–GFP does not display a punctate pattern and instead is distributed diffusely throughout the cytoplasm (but is excluded from yolk granules). (D) In response to Fz, Dsh(ΔDIX)–GFP relocalizes to the plasma membrane (shown) and is also present in filopodia (not shown). (E) Dsh(ΔDEP)–GFP localizes to the cytoplasm in a punctate pattern. (F) Dsh(ΔDEP)–GFP, however, does not relocalize to the plasma membrane in response to Fz and displays a punctate pattern similar to that seen in the absence of Fz. (G) Dsh(DEP+) is diffusely cytoplasmic in the absence of Fz, and is sufficient to promote membrane localization in the presence of Fz (H). Texas Red phalloidin was used to visualize cell outlines in A, C, E,and G.

References [+] :

Adler, Tissue polarity points from cells that have higher Frizzled levels towards cells that have lower Frizzled levels. 1997, Pubmed