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doi: 10.1242/10.1242/dev.00411

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Strabismus requires Flamingo and Prickle function to regulate tissue polarity in the Drosophila eye

Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA

View larger version (55K): [in a new window]   Fig. 1. fmi and pk mutations dominantly modify the sev-stbm eye phenotype. Tangential sections through adult eyes are shown in the top part of each panel and a schematic is given below, in which different chiral forms are shown in different colors. (A) In wild-type adult eyes, ommatidia in the dorsal hemisphere are oriented towards the dorsal pole while those in the ventral hemisphere are oriented towards the ventral pole. These fields of opposing ommatidial chirality are separated by the equator (yellow line). The inset illustrates the position of photoreceptors R1-R8 in a single ommatidium. (B-E) All sections are from the dorsal half of the eye. (B) sev-stbm. About 10% of ommatidia display errors in polarity, as illustrated by differently colored trapezoids. (C,D,E) Mutations in fmi enhance the sev-stbm phenotype. (C) sev-stbm/+; fmifrz3/+, (D) sev-stbm/+; fmi192 /+, (E) sev-stbm /+; fmiE59/+. Three fmi alleles, fmifrz3 (a hypomorphic allele), fmi192 and fmiE59 (both null alleles) dominantly enhance the sev-stbm phenotype about 3 fold. Yellow forms in the schematics denote symmetrical defects. (F) A hypomorphic pk allele, pkpk1, enhances the sev-stbm phenotype about 2.5 fold. (See Table 1 for quantitative data.) Blue and red trapezoids represent ommatidia in the dorsal and ventral hemispheres, respectively. Anterior to the right.

View larger version (73K): [in a new window]   Fig. 2. Genetic enhancement of fmi by stbm and stbm by pk. Tangential sections through adult eyes (left) and the corresponding schematics (right). (A) Approximately 12% of ommatidia adopt incorrect polarity in a fmifrz3/fmifrz3 hypomorphic mutant. (B) stbm153, fmifrz3/fmifrz3. Haploinsufficiency of stbm153, a hypomorphic allele of stbm, enhances the fmifrz3 homozygous phenotype 3 fold. (C) About 40% of ommatidia in a stbm153/stbm153 homozygote display defects in polarity (B. K. Grillo-Hill, unpublished). (D) Flies homozygous for both stbm153 and pkpk1 display an enhanced number of symmetrical defects (yellow) relative to stbm153 homozygotes. All sections shown are from the dorsal hemisphere, therefore all trapezoids should be blue. (See Table 2 for quantitative data.) Anterior to the right.

View larger version (96K): [in a new window]   Fig. 3. fmi null eyes exhibit a classical ommatidial polarity phenotype. Sections of adult eyes (left) and the corresponding schematics (right). (A,B) fmi192 mutant clones have a tissue polarity phenotype. Areas shaded in red represent wild-type tissue; white areas represent mutant clones and include both mutant and mosaic ommatidia. fmi192 clones close to the equator (B) have a stronger polarity phenotype. (C) EGUF-fmi192 eyes, which are completely mutant for fmi, also display a typical polarity phenotype. (See Table 3 for quantitative data.) Anterior to the right.

View larger version (175K): [in a new window]   Fig. 4. Stbm localization is dynamic in developing ommatidia. In all panels, anti-Arm, which outlines cells, is shown in red and anti-Stbm is shown in green. (A-C) Stbm is uniformly localized to the apical membranes of cells within, and one to two rows posterior to, the morphogenetic furrow. (D-F) By row 6, Stbm is localized strongly to the anterior membranes of R3 and R4, to the boundary between them (arrowhead), and to the tip of R8 where it contacts R1, R7 and R6 (arrow). Also by this point, Stbm has disappeared from the cell membranes of R8, R2 and R5. (G-I) Posterior region of developing eye imaginal disc showing Stbm localization in the cone cells. See text for details. Anterior to the right.

View larger version (119K): [in a new window]   Fig. 5. Fmi localization is dynamic throughout development and is dependent upon fz. (A) Wild-type third instar eye disc immunostained with anti-Fmi (white arrowhead indicates an R4 cell with a high level of Fmi). (B) High-magnification images of areas a-d in A. (a) Fmi is localized to all membranes of nascent photoreceptors in developing ommatidial clusters. (b) By row 6, Fmi is prominent at the membranes of R3 and R4 (white arrow indicates contact between R3 and R4) and at the point of contact between R1/R7/R6 and R8. (c) By row 8, Fmi is enhanced in R4 and by row 10 appears in punctate structures (d). (C) Fmi localization is disrupted in eye discs homozygous for fzKD4A (a null allele). (D) High-magnification images of areas a-d in C. (a) Fmi localization is unaffected ahead of the furrow (not shown) and in early ommatidial precursors. (b) Localization of Fmi is not affected at this stage. (c) Preferential accumulation of Fmi to R4 is abolished in the fzKD4A background. (d) Vesicle morphology is disrupted, primarily in the number, size and position of Fmi-containing vesicles. Scale bar: 5 µm. Anterior to the right.

View larger version (122K): [in a new window]   Fig. 6. Fmi is endocytosed. Bottom panels show high magnification images of ommatidia that correspond to the stages represented by the ommatidia in the boxes in top panels. (A) In wild type, Fmi localizes to large vesicles between the nuclei of R3 and R4. (B) In a shi2ts mutant heat-treated for 2 hours, the large vesicles seen in wild type have been replaced by small puncta decorating membranes. (C) In a hk11 mutant, the large MVB-like vesicles are also replaced with smaller puncta, although they are larger than those seen in shi mutants. Scale bar: 1 µm. Anterior to the right.

View larger version (81K): [in a new window]   Fig. 7. Stbm plays a role in Pk localization. (A) A schematic representation of a photoreceptor cluster in the third larval instar. (B-D) Wild-type disc and (E-G) stbm6cn disc, immunostained for Pk (B,E) and Arm (C,F). (D,G) Overlays of B and C, and E and F, respectively. Arrow in B indicates high levels of Pk staining at the contact between R1/R7/R6 and R8. (E-G) Levels of Pk are significantly diminished overall, but not abolished in R3 and R4. Pk staining at the contact between R1/R7/R6 and R8 is not detectable (arrowhead in E). In all panels, anti-Pk is shown in green and anti-Arm is shown in red. Anterior to the right.

View larger version (18K): [in a new window]   Fig. 8. A model for the asymmetric regulation of N by the tissue polarity proteins. At the junction of photoreceptors R3/R4, Fmi is anchored in both R3 and R4 via homophilic association. In the developing photoreceptor R3, Fmi, Diego, and Dsh form a complex in which N is bound to Dsh. However, in the developing R4, Fmi, Diego, and Dsh form a complex in which Pk and Stbm are bound to Dsh, thereby preventing N from binding to Dsh. Consequently, in R4, N is released from this membrane-bound complex and can signal at high levels.