Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
Author for correspondence (e-mail: helen.mcneill{at}cancer.org.uk)
![]() |
Summary |
---|
Key words: PCP, Planar cell polarity, Frizzled, Dishevelled
![]() |
Introduction |
---|
|
![]() |
Core PCP genes |
---|
Dishevelled (Dsh), another molecule involved in Wg signalling, is also required for tissue polarity (Theisen et al., 1994). However, like Fz, Dsh seems to act in a non-canonical pathway. Systematic analysis of Dsh domain structure and function has revealed that certain domains are crucial for its role in PCP, but are dispensable for Wg signalling (Axelrod et al., 1998
; Boutros et al., 1998
).
There are other core PCP genes that do not seem to have any function in the canonical Wg pathway. Prickle (Pk) is a LIM-domain-containing protein thought to negatively regulate the Fz/Dsh PCP pathway (Gubb et al., 1999; Tree et al., 2002
). Mutations in the atypical cadherin Flamingo (Fmi, also called Starry night) (Chae et al., 1999
; Usui et al., 1999
) and the putative transmembrane protein Strabismus (Stbm, also called Van Gogh) also disrupt polarity in many tissues, and hence belong to the core PCP pathway.
![]() |
Wing hair polarity |
---|
|
![]() |
Ommatidial polarity |
---|
PCP mutations can lead to very diverse alterations in the polarity of the ommatidia (Fig. 1). Ommatidia can be flipped along the D/V axis (e.g. for a dorsal ommatidium, the adoption of ventral polarity), or along the anterior-posterior (A/P) axis). They can lose their polarized, trapezoid form, resulting in symmetric ommatidia, and can display both under- and over-rotation defects. All these defects are visible in strong fz alleles. Other genes might affect only some of these aspects of PCP; for example, elements of the epidermal growth factor (EGF)/Ras pathway, such as Roulette (an allele of the EGF inhibitor Argos) and mitogen-activated protein (MAP) kinases such as Nemo can specifically effect rotation (Choi and Benzer, 1994; Yang et al., 1999
; Strutt and Strutt, 2002
; Brown and Freeman, 2003
; Gaengel and Mlodzik, 2003
). Mutations in the small GTPases RhoA and Rac and the secreted protein Scabrous also primarily affect rotation (Strutt et al., 1997
; Chou and Chien, 2002
), whereas loss of the atypical cadherins Fat (Ft) and Dachsous (Ds) lead to only D/V flips (Rawls et al., 2002
; Yang et al., 2002
).
An early step in establishing PCP in the eye is the definition of the equator. Iroquois transcription factors such as Mirror (Gomez-Skarmeta et al., 1996; McNeill et al., 1997; Yang et al., 1999
) are expressed only in the dorsal half of the eye, and establish the position of the equator through regulation of cell adhesion and by restricting expression of Fringe to the ventral half of the eye. This leads to activation of Notch at the presumptive equator (reviewed by Axelrod and McNeill, 2002
). Notch activation is thought to lead to the production at the equator of a diffusible factor, `Factor X'. Genetic data suggest that Factor X diffuses from the equator and binds to and activates Fz, resulting in a gradient of Fz activity. It is thought that this gradient of Fz activity gives positional information to developing ommatidia.
A great deal of work has elucidated how Fz signalling establishes the polarity of a single ommatidium. The key players are the photoreceptor cells R3 and R4. When clusters emerge from the morphogenetic furrow, the presumptive R3 cell (preR3) is closer to the midline than the preR4. Fz signalling is activated on both cells, but there is a bias for stronger levels of activation in preR3 rather than in preR4. According to the Factor X model, this is because the preR3 is closer to the midline, which is proposed to be the region of production for this signal. The cell with higher Fz activity will become R3, and the other cell will become R4 (Tomlinson and Struhl, 1999; Zheng et al., 1995
). It has also been shown that the cell with the higher Notch activity becomes the R4 cell. It is thought that regulation of Notch activity occurs by transcriptional regulation of a Notch ligand, Delta, by Fz signalling. Delta expression is higher in the preR3 cell, which is thought to activate Notch on the preR4 cell (Cooper and Bray, 1999
; Fanto and Mlodzik, 1999
). Recently, an alternative model has been proposed, suggesting that Notch activity in preR3 is downregulated by a direct interaction of Notch with Dsh (Strutt et al., 2002
). However, Notch activity is regulated, it is clear that the establishment of R3 versus R4 cell fate after Notch activation directs the polarity of the entire ommatidium.
The JNK pathway has also been implicated in regulating PCP in the eye, primarily on the basis of overexpression experiments (reviewed by Axelrod and McNeill, 2002). However, loss of Jun or its activating kinase Bsk, does not significantly affect PCP. This could be because there are redundant pathways that act in PCP, masking the jun and bsk phenotypes. The p38 pathway has been suggested to be this redundant pathway. However, it is also possible that jun and bsk are essential for the PCP phenotype that is caused by Dsh or Fz overexpression but not for the normal establishment of PCP. There is no evidence for a JNK pathway in PCP in the fly wing. Several studies have linked activation of the JNK pathway in vertebrates with convergent extension and have suggested a common Fz
Rho
JNK pathway (see below). However, in mammalian systems, JNK is primarily activated by Cdc42 and Rac, and not by Rho (Noselli and Agnes, 1999
). Although DN-Rac can induce polarity changes in the fly eye (Fanto et al., 2000
), loss of all Racs (Hakeda-Suzuki et al., 2002
) does not alter PCP, highlighting the caution needed in interpreting overexpression phenotypes.
![]() |
Asymmetric localization |
---|
Most PCP proteins are initially symmetrically distributed on the cell membranes. At 26-30 hours after pupation (APF), these proteins relocalize to specific membrane domains (Fig. 3A). The atypical cadherin Fmi becomes transiently localized on both the proximal and distal sides, and depleted from the anterior and posterior cell membranes (Usui et al., 1999). The ankyrin repeat protein Diego is also thought to accumulate on both proximal and distal membranes (Feiguin et al., 2001
). Fz and Dsh become localized only to the distal membrane, whereas Stbm and Pk localize solely on the proximal side (Axelrod, 2001
; Bastock et al., 2003
; Shimada et al., 2001
; Tree et al., 2002
). Interactions along the proximal-distal axis between proteins on the distal membrane of one cell and the proximal membrane of the next cell are thought to stabilize the system. Interestingly, the regulatory subunit of the protein phosphatase PP2A, encoded by widerborst (wdb), becomes localized to the distal side of the cell before there is any obvious asymmetric localization of Fz, Dsh, Pk or Stbm. Remarkably, Wdb localization undergoes a dramatic shift: at 8 APF, it is localized proximally, and only later switches to the distal side, where it colocalizes with microtubules (Hannus et al., 2002
). This suggests that some form of PCP is present well before the asymmetric localization of the core PCP proteins.
|
PCP proteins are also asymmetrically localized in the eye. However, in the eye, only a few cells in each ommatidial precluster show protein relocalization. Fz, Dsh, Fmi and Stbm are asymmetrically localized in the preR3 and preR4 cells as clusters begin their rotation (reviewed by McNeill, 2002) (Fig. 3B). Significantly, no such asymmetry is seen on the other photoreceptor cells, or in the cells surrounding the clusters. Fz and Dsh become localized at the preR3/preR4 boundary on the preR3 side, and on the anterior and polar side of the preR4 membrane. Fmi is localized on both the sides of the preR3/preR4 boundary, whereas Stbm is localized only on the preR4 side of the boundary. It is not known where Pk is localized in the eye but it is likely that a feedback loop similar to that proposed in the wing also functions in the eye. However, this can happen only at one cellular interface: that found between the preR3 and preR4 cells. This is very different from the wing, where all cells show asymmetric localization of these PCP proteins.
![]() |
How is positional information sensed? |
---|
Initial studies describing the role of ft and ds in the eye focused on their role in R3/R4 fate determination. Yang et al. reported that Ft biases the cells in the preR3/preR4 pair towards R3 cell fate, whereas Ds biases towards R4 identity (Yang et al., 2002). Ds is expressed in a gradient in the eye: there are low levels of Ds at the equatorial region, and high levels at the poles (Fig. 4). Therefore, the cell closest to the pole (the R4 cell) would have higher levels of Ds than would the cell closer to the equator (the R3 cell). The requirement for Ft in the R3 cell resembles that of Fz, and Yang and coworkers proposed that Ft cell-autonomously regulates Fz activity (Yang et al., 2002
).
|
There are also particularly striking non-cell-autonomous polarity effects caused by loss of ft or ds. For example, although ommatidia inside a ft mutant clone tend to have randomized polarity, ommatidia on one side of a ft clone, the side closest to the equator, have their polarity rescued by wild-type tissue. Bu contrast, wild-type ommatidia on the side furthest from the equator have their polarity disrupted by the nearby mutant cells. This is very similar to the phenotype of loss of non-cell-autonomous fz function, and has led to the suggestion that Ft and Ds control the production of Factor X. The finding that the cytoplasmic domain of Ft binds directly to a transcriptional repressor, Atrophin (Atro), supports this hypothesis (Fanto et al., 2003). Ds binding to Ft is thought to alter Atro transcriptional activity and thereby the production of Factor X. Ft and Atro transcriptionally control the production of one known PCP morphogen, Four-Jointed (Fj). fj is expressed in a gradient in the eye disc with highest levels around the equator (Zeidler et al., 1999
) (Fig. 4). Loss of fj in clones can reorient adjacent wild-type ommatidia, as can ectopic expression of fj. Intriguingly, eyes entirely lacking fj display very weak PCP defects, indicating that there are redundant mechanisms that control PCP. Genetic epistasis studies indicate that Fj acts upstream of Ds, which is in turn upstream of Ft/Atro. However, ds, ft and atro also control fj transcription, which suggests that feedback loops operate in PCP establishment in the eye.
In the wing, these genes also play an important role in PCP. Ds and Fj are expressed in opposing gradients in the wing, as in the eye (Fig. 4). Careful analysis of their subcellular distributions showed that, unlike other core PCP proteins, Ds and Ft do not appear to localize asymmetrically along the proximal-distal axis within wing cells. They are located just above the zonula adherens, where Fz, Dsh and Pk localize, and their localization is not affected in fz clones. Together with epistasis experiments, the data suggest that Fj, Ft, Ds and Atro act upstream of Fz and the other tissue polarity genes, whose activity and localization is randomized but not blocked by mutations in these genes.
![]() |
An eye for an eye, a wing for a wing |
---|
There appear to be significant differences in the functions of PCP genes in different tissues. For example, ft clones perturb hair polarity only in particular regions of the wing (Strutt and Strutt, 2002), but no such spatial restrictions have been reported in the eye. Furthermore, several reports agree that small ft or ds clones have little effect on wing hair polarity (Adler et al., 1998
; Ma et al., 2003
; Strutt and Strutt, 2002
), whereas quite small clones can disrupt PCP in the eye. Similarly, in the eye, both fj and fz cause non-cell-autonomous polarity inversions on the same side of clones (Zeidler et al., 1999
; Zheng et al., 1995
) whereas, in the wing, fj and fz cause non-cell-autonomous polarity phenotypes on opposite sides of clones (Vinson and Adler, 1987
; Zeidler et al., 2000
). We believe that these differences between the two systems should always be kept in mind when proposing `one-size-fits-all' mechanisms for PCP establishment. Although the cross comparison of data and interpretations between the two systems has been intense and proven to be extremely fruitful, the field has perhaps reached a point where differences need to be taken into greater account.
![]() |
Dominos versus the mysterious Factor X |
---|
Alternative models rely on the presence of a Factor X that activates Fz, and some have even proposed the existence of a Factor Z, which would be produced as a result of Fz activity and would relay the signal to Fz receptors on that cell and on neighbouring cells (Adler et al., 2000). Interestingly, views in the field about Factor X have changed. Initially, it was proposed to be a morphogen-like molecule produced in a few crucial cells (the most proximal cells in the wing or at the D/V midline in the eye) and able to diffuse in a gradient over long distances. More recent views propose that this activity may be a short-range diffusible factor produced throughout the epithelium but in different amounts according to the position of the different cells (Fanto et al., 2003
).
We think a model relying on Factor X is necessary to explain the establishment of PCP in the eye. Here, the domino model is less appealing, because only a few cells in the tissue appear to be internally polarized and asymmetrically localize Fz/Dsh/Stbm. The preR3 and preR4 cells are surrounded by non-polarized cells, which provide a formidable obstacle to the domino model. Moreover, such models leave unresolved the problem of how a cluster communicates and coordinates its polarity with other clusters. As previously mentioned, a candidate for controlling Factor X expression in the eye is the transcriptional repressor Atro. Understanding how Atro controls Factor X and PCP awaits the discovery of the mysterious Factor X.
![]() |
Planar polarity in vertebrates |
---|
|
Many of the PCP genes also function in vertebrate embryos during convergent extension, a process in which a tissue narrows in one axis and elongates in a perpendicular axis. Convergent extension is driven by the polarized rearrangement of cells within a tissue. In fish and mice, mutants in many PCP genes disrupt convergent extension. The first evidence that PCP genes might act in convergent extension was the finding that Dsh (acting through the DEP domain, which has been implicated in PCP signalling) is essential for polarized cell movements (Heisenberg et al., 2000; Wallingford et al., 2000
). Subsequently, other PCP molecules, such as Stbm, were also found to be essential for convergent extension (reviewed by Mlodzik, 2002
). Interestingly, these examples of cell migration are mediated by polarized protrusive activity of individual cells; however, the migrating unit is the whole tissue. This suggests that PCP signalling involves the establishment of signalling between cells that confers a collective identity upon them. The result would be a properly organized tissue able to act as a single entity, whether that tissue migrates or forms a planar organized structure.
![]() |
Perspectives |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
Adler, P. N., Vinson, C., Park, W. J., Conover, S. and Klein, L. (1990). Molecular structure of frizzled, a Drosophila tissue polarity gene. Genetics 126, 401-416.
Adler, P. N., Krasnow, R. E. and Liu, J. (1997). Tissue polarity points from cells that have higher Frizzled levels towards cells that have lower Frizzled levels. Curr. Biol. 7, 940-949.[Medline]
Adler, P. N., Charlton, J. and Liu, J. (1998). Mutations in the cadherin superfamily member gene dachsous cause a tissue polarity phenotype by altering frizzled signaling. Development 125, 959-968.
Adler, P. N., Taylor, J. and Charlton, J. (2000). The domineering non-autonomy of frizzled and van Gogh clones in the Drosophila wing is a consequence of a disruption in local signaling. Mech. Dev. 96, 197-207.[CrossRef][Medline]
Axelrod, J. D. (2001). Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev. 15, 1182-1187.
Axelrod, J. D. and McNeill, H. (2002). Coupling planar cell polarity signaling to morphogenesis. Scientific World Journal 2, 434-454.[Medline]
Axelrod, J. D., Miller, J. R., Shulman, J. M., Moon, R. T. and Perrimon, N. (1998). Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 12, 2610-2622.
Bastock, R., Strutt, H. and Strutt, D. (2003). Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development 130, 3007-3014.
Boutros, M., Paricio, N., Strutt, D. I. and Mlodzik, M. (1998). Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94, 109-118.[Medline]
Brown, K. E. and Freeman, M. (2003). Egfr signalling defines a protective function for ommatidial orientation in the Drosophila eye. Development 130, 5401-5412
Casal, J., Struhl, G. and Lawrence, P. A. (2002). Developmental compartments and planar polarity in Drosophila. Curr. Biol. 12, 1189-1198.[CrossRef][Medline]
Chae, J., Kim, M. J., Goo, J. H., Collier, S., Gubb, D., Charlton, J., Adler, P. N. and Park, W. J. (1999). The Drosophila tissue polarity gene starry night encodes a member of the protocadherin family. Development 126, 5421-5429.
Choi, K. W. and Benzer, S. (1994). Rotation of photoreceptor clusters in the developing Drosophila eye requires the nemo gene. Cell 78, 125-136.[Medline]
Chou, Y. H. and Chien, C. T. (2002). Scabrous controls ommatidial rotation in the Drosophila compound eye. Dev. Cell. 3, 839-850.[Medline]
Cooper, M. T. and Bray, S. J. (1999). Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye. Nature 397, 526-530.[CrossRef][Medline]
Curtin, J. A., Quint, E., Tsipouri, V., Arkell, R. M., Cattanach, B., Copp, A. J., Henderson, D. J., Spurr, N., Stanier, P., Fisher, E. M. et al. (2003). Mutation of celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129-1133.[CrossRef][Medline]
Eaton, S. (1997). Planar polarization of Drosophila and vertebrate epithelia. Curr. Opin. Cell Biol. 9, 860-866.[CrossRef][Medline]
Eaton, S., Wepf, R. and Simons, K. (1996). Roles for Rac1 and Cdc42 in planar polarization and hair outgrowth in the wing of Drosophila. J. Cell Biol. 135, 1277-1289.[Abstract]
Fanto, M. and Mlodzik, M. (1999). Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye. Nature 397, 523-526.[CrossRef][Medline]
Fanto, M., Weber, U., Strutt, D. I. and Mlodzik, M. (2000). Nuclear signaling by Rac and Rho GTPases is required in the establishment of epithelial planar polarity in the Drosophila eye. Curr. Biol. 10, 979-988.[CrossRef][Medline]
Fanto, M., Clayton, L., Meredith, J., Hardiman, K., Charroux, B., Kerridge, S. and McNeill, H. (2003). The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130, 763-774.
Feiguin, F., Hannus, M., Mlodzik, M. and Eaton, S. (2001). The ankyrin repeat protein Diego mediates Frizzled-dependent planar polarization. Dev. Cell 1, 93-101.[Medline]
Gaengel, K. and Mlodzik, M. (2003). Egfr signaling regulates ommatidial rotation and cell motility in the Drosophila eye via MAPK/Pnt signaling and the Ras effector Canoe/AF6. Development 130, 5413-5423.
Gomez-Skarmeta, J. L., Diez del Corral, R., de la Calle-Mustienes, E., Ferre-Marco, D. and Modolell, J. (2003). Araucan and caupolican, two members of the novel iroquois complex, encode homeoproteins that control proneural and vein-forming genes. Cell 85, 95-105
Gubb, D. and Garcia-Bellido, A. (1982). A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster. J. Embryol. Exp. Morphol. 68, 37-57.[Medline]
Gubb, D., Green, C., Huen, D., Coulson, D., Johnson, G., Tree, D., Collier, S. and Roote, J. (1999). The balance between isoforms of the prickle LIM domain protein is critical for planar polarity in Drosophila imaginal discs. Genes Dev. 13, 2315-2327.
Hakeda-Suzuki, S., Ng, J., Tzu, J., Dietzl, G., Sun, Y., Harms, M., Nardine, T., Luo, L. and Dickson, B. J. (2002). Rac function and regulation during Drosophila development. Nature 416, 438-442.[CrossRef][Medline]
Hannus, M., Feiguin, F., Heisenberg, C. P. and Eaton, S. (2002). Planar cell polarization requires Widerborst, a B' regulatory subunit of protein phosphatase 2A. Development 129, 3493-3503.[Medline]
Heisenberg, C. P., Tada, M., Rauch, G. J., Saude, L., Concha, M. L., Geisler, R., Stemple, D. L., Smith, J. C. and Wilson, S. W. (2000). Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 405, 76-81.[CrossRef][Medline]
Held, L. I., Jr, Duarte, C. M. and Derakhshanian, K. (1986). Extra joints and misoriented bristles on Drosophila legs. Prog. Clin. Biol. Res. 217A, 293-296.[Medline]
Hulsken, J. and Behrens, J. (2002). The Wnt signalling pathway. J. Cell Sci. 113, 3545-3546.
Ma, D., Yang, C. H., McNeill, H., Simon, M. A. and Axelrod, J. D. (2003). Fidelity in planar cell polarity signalling. Nature 421, 543-547.[CrossRef][Medline]
McNeill, H., Yang, C. H., Brodsky, M., Ungos, J. and Simon, M. A. (1997). Mirror encodes a novel PBX-class homeoprotein that functions in the definition of the dorsal-ventral border in the Drosophila eye. Genes Dev. 11, 1073-1082.[Abstract]
McNeill, H. (2002). Planar polarity: location, location, location. Curr. Biol. 12, R449-451.[CrossRef][Medline]
Mlodzik, M. (2002). Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet. 18, 564-571.[CrossRef][Medline]
Montcouquiol, M., Rachel, R. A., Lanford, P. J., Copeland, N. G., Jenkins, N. A. and Kelley, M. W. (2003). Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173-177.[CrossRef][Medline]
Noselli, S. and Agnes, F. (1999). Roles of the JNK signaling pathway in Drosophila morphogenesis. Curr. Opin. Genet. Dev. 9, 466-472.[CrossRef][Medline]
Park, W. J., Liu, J. and Adler, P. N. (1994a). Frizzled gene expression and development of tissue polarity in the Drosophila wing. Dev. Genet. 15, 383-389.[Medline]
Park, W. J., Liu, J. and Adler, P. N. (1994b). The frizzled gene of Drosophila encodes a membrane protein with an odd number of transmembrane domains. Mech. Dev. 45, 127-137.[CrossRef][Medline]
Rawls, A. S., Guinto, J. B. and Wolff, T. (2002). The cadherins fat and dachsous regulate dorsal/ventral signaling in the Drosophila eye. Curr. Biol. 12, 1021-1026.[CrossRef][Medline]
Shimada, Y., Usui, T., Yanagawa, S., Takeichi, M. and Uemura, T. (2001). Asymmetric colocalization of Flamingo, a seven-pass transmembrane cadherin, and Dishevelled in planar cell polarization. Curr. Biol. 11, 859-863.[CrossRef][Medline]
Strutt, D. I., Weber, U. and Mlodzik, M. (1997). The role of RhoA in tissue polarity and Frizzled signalling. Nature 387, 292-295.[CrossRef][Medline]
Strutt, D., Johnson, R., Cooper, K. and Bray, S. (2002). Asymmetric localization of frizzled and the determination of notch-dependent cell fate in the Drosophila eye. Curr. Biol. 12, 813-824.[CrossRef][Medline]
Strutt, H. and Strutt, D. (2002). Nonautonomous planar polarity patterning in Drosophila: dishevelled-independent functions of frizzled. Dev. Cell 3, 851-863.[Medline]
Theisen, H., Purcell, J., Bennett, M., Kansagara, D., Syed, A. and Marsh, J. L. (1994). dishevelled is required during wingless signaling to establish both cell polarity and cell identity. Development 120, 347-360.
Tomlinson, A. and Struhl, G. (1999). Decoding vectorial information from a gradient: sequential roles of the receptors Frizzled and Notch in establishing planar polarity in the Drosophila eye. Development 126, 5725-5738.
Tree, D. R., Shulman, J. M., Rousset, R., Scott, M. P., Gubb, D. and Axelrod, J. D. (2002). Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 109, 371-381.[Medline]
Turner, C. M. and Adler, P. N. (1995). Morphogenesis of Drosophila pupal wings in vitro. Mech. Dev. 52, 247-255.[CrossRef][Medline]
Usui, T., Shima, Y., Shimada, Y., Hirano, S., Burgess, R. W., Schwarz, T. L., Takeichi, M. and Uemura, T. (1999). Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585-595.[Medline]
Vinson, C. R. and Adler, P. N. (1987). Directional non-cell autonomy and the transmission of polarity information by the frizzled gene of Drosophila. Nature 1329, 549-551.
Wallingford, J. B., Rowning, B. A., Vogeli, K. M., Rothbacher, U., Fraser, S. E. and Harland, R. M. (2000). Dishevelled controls cell polarity during Xenopus gastrulation. Nature 405, 81-85.[CrossRef][Medline]
Wehrli, M. and Tomlinson, A. (1998). Independent regulation of anterior/posterior and equatorial/polar polarity in the Drosophila eye; evidence for the involvement of Wnt signaling in the equatorial/polar axis. Development 125, 1421-1432.
Winter, C. G., Wang, B., Ballew, A., Royou, A., Karess, R., Axelrod, J. D. and Luo, L. (2001). Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105, 81-91.[CrossRef][Medline]
Wong, L. L. and Adler, P. N. (1993). Tissue polarity genes of Drosophila regulate the subcellular location for prehair initiation in pupal wing cells. J. Cell Biol. 123, 209-221.[Abstract]
Yang, C. H., Simon, M. A. and McNeill, H. (1999). Mirror controls planar polarity and equator formation through repression of fringe expression and through control of cell affinities. Development 126, 5857-5866.
Yang, C. H., Axelrod, J. D. and Simon, M. A. (2002). Regulation of Frizzled by fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell 108, 675-688.[Medline]
Zeidler, M. P., Perrimon, N. and Strutt, D. I. (1999). The four-jointed gene is required in the Drosophila eye for ommatidial polarity specification. Curr. Biol. 9, 1363-1372.[CrossRef][Medline]
Zeidler, M. P., Perrimon, N. and Strutt, D. I. (2000). Multiple roles for four-jointed in planar polarity and limb patterning. Dev. Biol. 228, 181-196.[CrossRef][Medline]
Zheng, L., Zhang, J. and Carthew, R. W. (1995). frizzled regulates mirror-symmetric pattern formation in the Drosophila eye. Development 121, 3045-3055.