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First published online August 18, 2003
doi: 10.1242/10.1242/dev.00695

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Frizzled signalling and cell polarisation in Drosophila and vertebrates

Centre for Developmental Genetics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK e-mail: d.strutt{at}sheffield.ac.uk

View larger version (17K): [in a new window]   Fig. 1. Canonical and non-canonical Frizzled signalling pathways. (A) A simplified scheme of the canonical Wnt signalling pathway. In this pathway, a Wnt ligand binds to a Frizzled (Fz) family receptor and a co-receptor of the low density lipoprotein receptor-related protein (LRP) family. In canonical Wnt pathways, Dishevelled (Dsh) and ß-catenin are characteristically required to transduce the Wnt signal, leading to a transcriptional response mediated by transcription factors of the ternary complex factor (TCF)/lymphoid enhancer factor 1 (LEF1) family. Fz receptors might also couple to heterotrimeric G proteins in this pathway (see text for more details). (B) Planar polarity involves a non-canonical ß-catenin-independent Wnt/Fz pathway that requires Dsh. A Wnt ligand for this pathway has yet to be identified in Drosophila ('?'), although Wnt ligands have been found to activate an analogous pathway in vertebrates. There is also no evidence, as yet, for heterotrimeric G proteins being involved. This pathway involves the core planar polarity proteins (blue) Flamingo/Starry Night (Fmi/Stan), Van Gogh/Strabismus (Vang/Stbm), Prickle (Pk) and Diego (Dgo). These proteins are thought to modulate the activity of this pathway by forming a multiprotein complex with Fz/Dsh that spans cell-cell junctions, rather than being cascade components. Fmi/Stan and Vang/Stbm are both multipass transmembrane proteins, whereas Pk and Dgo are cytoplasmic proteins. The prickle (pk) locus produces two protein isoforms, Pk and Spiny Legs (Sple), which vary in activity from tissue to tissue (only Pk is shown here for simplicity). (C) The Wnt/Ca2+ pathway probably signals via heterotrimeric G-proteins (, ß, subunits), to mobilise intracellular Ca2+ and, in some contexts, to stimulate protein kinase C (PKC). Whether this pathway requires Dsh remains controversial (see text for more details). In vertebrates, Wnt/Ca2+ signalling is activated by the same ligands as the planar polarity pathway, suggesting that these pathways may overlap to some extent.

View larger version (36K): [in a new window]   Fig. 2. Planar polarity and fz phenotypes in the Drosophila wing and eye. (A) During pupal life in the wild-type wing (top), hairs form at the distal vertex on the apical surface of each cell and point distally. In the absence of frizzled (fz) activity (bottom), hairs form in the centre of cells and ultimately adopting swirling patterns in the adult wing. (B) A clone of cells in the wing lacking fz activity (pink) shows both autonomous and non-autonomous polarity phenotypes. Cells in the clone form hairs in the centre of the cell. Cells around it form hairs that point towards the clone. (C) In the eye, ommatidia are gradually assembled by the recruitment of eight photoreceptor cells (R1-R8), and become polarised. fz activity is required in the R3/R4 cell pair (light green) for a correct chirality decision to occur, such that one cell takes on the R3 fate (dark green) and the ommatidium rotates 90° clockwise in the dorsal half of the eye or anticlockwise in the ventral half. Absence of fz activity leads to a randomised choice (or no choice) of R3 fate and a randomised degree of rotation that is either greater or less than 90°.

View larger version (34K): [in a new window]   Fig. 3. Asymmetric localisation of core planar polarity proteins in the Drosophila wing and eye. (A) Distribution of core planar polarity proteins in cells of the pupal wing between 24 and 32 hours after prepupa formation (APF). Frizzled (Fz) and Flamingo/Starry Night (Fmi/Stan) are found in distal apicolateral membranes at the level of the adherens junctions, and Van Gogh/Strabismus (Vang/Stbm) and Fmi/Stan are found in proximal membranes. Other proteins are recruited from the cytoplasm to the cell cortex either distally [Dishevelled (Dsh)] or proximally [Prickle (Pk)], or both [Diego (Dgo)]. Actin accumulates and hairs form at the distal cell vertex at 32 hours APF. (B) Comparison of Fz and Vang/Stbm distribution in the wing and eye. Fz is distal and Vang is proximal in pupal wing cells. In the third instar eye disc, Fz is localised on the R3 side of the R3/R4 cell-cell boundary and Vang/Stbm is localised on the R4 side. (Fz and Vang/Stbm are probably also on other membranes of these cells, but this has not been fully characterised.) Thus, an intercellular complex forms across the R3/R4 cell-cell boundary that is probably functionally equivalent to the asymmetric complex across distal-proximal cell boundaries in the wing. (C) Loss of Fmi/Stan largely blocks Fz and Vang/Stbm recruitment to apicolateral cell regions (right, top and bottom). Loss of Dsh, Pk or Dgo blocks the formation of asymmetric proximodistal complexes between 18 and 32 hours APF (middle, top and bottom), resulting in Fz and Vang/Stbm remaining distributed around the circumference of the cells. Photomicrographs at the bottom are confocal sections through the apical regions of pupal wing cells at 28 hours of pupal life, showing Fz-GFP distribution in the adherens junction zone in wild type (left), in a pkpk-sple-13 mutant (middle) and in a fmiE59 mutant (right).

View larger version (38K): [in a new window]   Fig. 4. Polarisation of cells in convergent extension of vertebrate embryos. Simplified scheme of convergent extension in the mesoderm of Xenopus during gastrulation. Cells become polarised in a bipolar fashion on the mediolateral axis and intercalate, such that they converge together on the mediolateral axis and the tissue extends on the anteroposterior axis.