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• W4310861367 abstract "•dAbl negatively regulates ommatidial rotation through β-catenin at adherens junctions•dAbl localizes apically in R4, but not R3, during ommatidial rotation•Apical localization and activity of dAbl requires Notch signaling•dAbl interacts genetically and physically with Notch during ommatidial rotation A collective cell motility event that occurs during Drosophila eye development, ommatidial rotation (OR), serves as a paradigm for signaling-pathway-regulated directed movement of cell clusters. OR is instructed by the EGFR and Notch pathways and Frizzled/planar cell polarity (Fz/PCP) signaling, all of which are associated with photoreceptor R3 and R4 specification. Here, we show that Abl kinase negatively regulates OR through its activity in the R3/R4 pair. Abl is localized to apical junctional regions in R4, but not in R3, during OR, and this apical localization requires Notch signaling. We demonstrate that Abl and Notch interact genetically during OR, and Abl co-immunoprecipitates in complexes with Notch in eye discs. Perturbations of Abl interfere with adherens junctional organization of ommatidial preclusters, which mediate the OR process. Together, our data suggest that Abl kinase acts directly downstream of Notch in R4 to fine-tune OR via its effect on adherens junctions. A collective cell motility event that occurs during Drosophila eye development, ommatidial rotation (OR), serves as a paradigm for signaling-pathway-regulated directed movement of cell clusters. OR is instructed by the EGFR and Notch pathways and Frizzled/planar cell polarity (Fz/PCP) signaling, all of which are associated with photoreceptor R3 and R4 specification. Here, we show that Abl kinase negatively regulates OR through its activity in the R3/R4 pair. Abl is localized to apical junctional regions in R4, but not in R3, during OR, and this apical localization requires Notch signaling. We demonstrate that Abl and Notch interact genetically during OR, and Abl co-immunoprecipitates in complexes with Notch in eye discs. Perturbations of Abl interfere with adherens junctional organization of ommatidial preclusters, which mediate the OR process. Together, our data suggest that Abl kinase acts directly downstream of Notch in R4 to fine-tune OR via its effect on adherens junctions. Cells often possess directional features that play essential roles during development, function, and homeostasis of organs and tissues. Cellular polarity across the plane of tissues, referred to as planar cell polarity (PCP), provides cells with positional information thereby allowing them to orient with respect to the body and tissue axes.1Humphries A.C. Mlodzik M. From instruction to output: Wnt/PCP signaling in development and cancer.Curr. Opin. Cell Biol. 2018; 51: 110-116https://doi.org/10.1016/j.ceb.2017.12.005Crossref PubMed Scopus (83) Google Scholar,2Goodrich L.V. Strutt D. Principles of planar polarity in animal development.Development. 2011; 138: 1877-1892https://doi.org/10.1242/dev.054080Crossref PubMed Scopus (420) Google Scholar,3Peng Y. Axelrod J.D. Asymmetric protein localization in planar cell polarity: mechanisms, puzzles, and challenges.Curr. Top. Dev. Biol. 2012; 101: 33-53https://doi.org/10.1016/B978-0-12-394592-1.00002-8Crossref PubMed Scopus (67) Google Scholar,4Adler P.N. The frizzled/stan pathway and planar cell polarity in the Drosophila wing.Curr. Top. Dev. Biol. 2012; 101: 1-31https://doi.org/10.1016/B978-0-12-394592-1.00001-6Crossref PubMed Scopus (92) Google Scholar PCP polarization and cellular orientation are also key for directed cellular movement within tissues.1Humphries A.C. Mlodzik M. From instruction to output: Wnt/PCP signaling in development and cancer.Curr. Opin. Cell Biol. 2018; 51: 110-116https://doi.org/10.1016/j.ceb.2017.12.005Crossref PubMed Scopus (83) Google Scholar,5Davey C.F. Moens C.B. Planar cell polarity in moving cells: think globally, act locally.Development. 2017; 144: 187-200https://doi.org/10.1242/dev.122804Crossref PubMed Scopus (66) Google Scholar,6Butler M.T. Wallingford J.B. Planar cell polarity in development and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 375-388https://doi.org/10.1038/nrm.2017.11Crossref PubMed Scopus (269) Google Scholar PCP has been best studied in Drosophila and its establishment is mediated by a specific set of evolutionarily conserved “core PCP” proteins, which include the transmembrane proteins Frizzled (Fz), Van Gogh (Vang; Vangl in vertebrates, also known as Stbm in Drosophila), and Flamingo (Fmi; Celsr in vertebrates) and the cytoplasmic factors Dishevelled (Dsh; Dvl in vertebrates), Diego (Dgo; Diversin/Inversin in vertebrates), and Prickle (Pk).1Humphries A.C. Mlodzik M. From instruction to output: Wnt/PCP signaling in development and cancer.Curr. Opin. Cell Biol. 2018; 51: 110-116https://doi.org/10.1016/j.ceb.2017.12.005Crossref PubMed Scopus (83) Google Scholar,2Goodrich L.V. Strutt D. Principles of planar polarity in animal development.Development. 2011; 138: 1877-1892https://doi.org/10.1242/dev.054080Crossref PubMed Scopus (420) Google Scholar,7Wu J. Mlodzik M. A quest for the mechanism regulating global planar cell polarity of tissues.Trends Cell Biol. 2009; 19: 295-305https://doi.org/10.1016/j.tcb.2009.04.003Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar During PCP establishment, interactions among these core factors lead to the formation of asymmetrically localized complexes of Fz-Dsh-Dgo and Vang-Pk on opposing sides of cells, which are stabilized via intercellular homophillic adhesion of Fmi between neighboring cells across apical junctional membranes. These complexes form separate signaling units, interacting with their set of effector proteins and thus initiate distinct tissue and cell type-specific responses.1Humphries A.C. Mlodzik M. From instruction to output: Wnt/PCP signaling in development and cancer.Curr. Opin. Cell Biol. 2018; 51: 110-116https://doi.org/10.1016/j.ceb.2017.12.005Crossref PubMed Scopus (83) Google Scholar,4Adler P.N. The frizzled/stan pathway and planar cell polarity in the Drosophila wing.Curr. Top. Dev. Biol. 2012; 101: 1-31https://doi.org/10.1016/B978-0-12-394592-1.00001-6Crossref PubMed Scopus (92) Google Scholar,7Wu J. Mlodzik M. A quest for the mechanism regulating global planar cell polarity of tissues.Trends Cell Biol. 2009; 19: 295-305https://doi.org/10.1016/j.tcb.2009.04.003Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar PCP-induced downstream effector cascades can range from the (re)organization of cytoskeletal elements and the remodeling of cell adhesion complexes, to transcriptional regulation and associated cell fate changes.1Humphries A.C. Mlodzik M. From instruction to output: Wnt/PCP signaling in development and cancer.Curr. Opin. Cell Biol. 2018; 51: 110-116https://doi.org/10.1016/j.ceb.2017.12.005Crossref PubMed Scopus (83) Google Scholar,4Adler P.N. The frizzled/stan pathway and planar cell polarity in the Drosophila wing.Curr. Top. Dev. Biol. 2012; 101: 1-31https://doi.org/10.1016/B978-0-12-394592-1.00001-6Crossref PubMed Scopus (92) Google Scholar,5Davey C.F. Moens C.B. Planar cell polarity in moving cells: think globally, act locally.Development. 2017; 144: 187-200https://doi.org/10.1242/dev.122804Crossref PubMed Scopus (66) Google Scholar,8Jenny A. Planar cell polarity signaling in the Drosophila eye.Curr. Top. Dev. Biol. 2010; 93: 189-227https://doi.org/10.1016/B978-0-12-385044-7.00007-2Crossref PubMed Scopus (66) Google Scholar,9Devenport D. Tissue morphodynamics: translating planar polarity cues into polarized cell behaviors.Semin. Cell Dev. Biol. 2016; 55: 99-110https://doi.org/10.1016/j.semcdb.2016.03.012Crossref PubMed Scopus (36) Google Scholar In Drosophila, eye development is particularly well suited to study several aspects of PCP signaling, as it entails PCP-dependent cell fate differentiation and cell motility processes.8Jenny A. Planar cell polarity signaling in the Drosophila eye.Curr. Top. Dev. Biol. 2010; 93: 189-227https://doi.org/10.1016/B978-0-12-385044-7.00007-2Crossref PubMed Scopus (66) Google Scholar,10Mlodzik M. Planar polarity in the Drosophila eye: a multifaceted view of signaling specificity and cross-talk.EMBO J. 1999; 18: 6873-6879https://doi.org/10.1093/emboj/18.24.6873Crossref PubMed Scopus (150) Google Scholar,11Strutt H. Strutt D. Polarity determination in the Drosophila eye.Curr. Opin. Genet. Dev. 1999; 9: 442-446https://doi.org/10.1016/S0959-437X(99)80067-7Crossref PubMed Scopus (69) Google Scholar The Drosophila eye consists of ∼800 highly regularly arranged ommatidia, each of which is composed of 8 photoreceptor (R cell) neurons (R1–R8), arranged into a defined invariant trapezoidal pattern, and 12 accessory (cone, pigment, and bristle) cells.12Tomlinson A. Ready D.F. Neuronal differentiation in Drosophila ommatidium.Dev. Biol. 1987; 120: 366-376https://doi.org/10.1016/0012-1606(87)90239-9Crossref PubMed Scopus (407) Google Scholar,13Wolff T. Ready D.F. The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave.Development. 1991; 113: 841-850Crossref PubMed Google Scholar During larval stages, the eye develops from an epithelial imaginal disc, which is initially composed of identical pluripotent precursor cells. As a wave of cell proliferation and differentiation (referred to as morphogenetic furrow [MF]) travels across the disc from posterior to anterior, regularly spaced preclusters of differentiating cells start to form in its wake that will subsequently mature into ommatidial clusters (and ommatidia in the adult).12Tomlinson A. Ready D.F. Neuronal differentiation in Drosophila ommatidium.Dev. Biol. 1987; 120: 366-376https://doi.org/10.1016/0012-1606(87)90239-9Crossref PubMed Scopus (407) Google Scholar,13Wolff T. Ready D.F. The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave.Development. 1991; 113: 841-850Crossref PubMed Google Scholar,14Cagan R.L. Ready D.F. The emergence of order in the Drosophila pupal retina.Dev. Biol. 1989; 136: 346-362https://doi.org/10.1016/0012-1606(89)90261-3Crossref PubMed Scopus (339) Google Scholar,15Roignant J.Y. Treisman J.E. Pattern formation in the Drosophila eye disc.Int. J. Dev. Biol. 2009; 53: 795-804https://doi.org/10.1387/ijdb.072483jrCrossref PubMed Scopus (121) Google Scholar At the 5-cell precluster stage, differential specification of the R3/R4 cell pair requires asymmetric Fz/PCP signaling followed by directional Notch pathway activation within the pair and EGFR signaling, breaking the initial symmetry of the precluster.16Weber U. Pataki C. Mihaly J. Mlodzik M. Combinatorial signaling by the Frizzled/PCP and Egfr pathways during planar cell polarity establishment in the Drosophila eye.Dev. Biol. 2008; 316: 110-123Crossref PubMed Scopus (37) Google Scholar,17Weber U. Paricio N. Mlodzik M. Jun mediates Frizzled-induced R3/R4 cell fate distinction and planar polarity determination in the Drosophila eye.Development. 2000; 127: 3619-3629Crossref PubMed Google Scholar,18Fanto M. Mlodzik M. Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye.Nature. 1999; 397: 523-526https://doi.org/10.1038/17389Crossref PubMed Scopus (185) Google Scholar,19Cooper M.T. Bray S.J. Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye.Nature. 1999; 397: 526-530https://doi.org/10.1038/17395Crossref PubMed Scopus (209) Google Scholar,20Tomlinson A. Struhl G. Decoding vectorial information from a gradient: sequential roles of the receptors Frizzled and Notch in establishing planar polarity in the Drosophila eye.Development. 1999; 126: 5725-5738Crossref PubMed Google Scholar Differential specification of R3 and R4 fates also generates the directional cues that instruct the subsequent rotation of the precluster toward the dorsal-ventral (D/V) midline, often referred to as the equator, in a process called ommatidial rotation (OR).8Jenny A. Planar cell polarity signaling in the Drosophila eye.Curr. Top. Dev. Biol. 2010; 93: 189-227https://doi.org/10.1016/B978-0-12-385044-7.00007-2Crossref PubMed Scopus (66) Google Scholar,10Mlodzik M. Planar polarity in the Drosophila eye: a multifaceted view of signaling specificity and cross-talk.EMBO J. 1999; 18: 6873-6879https://doi.org/10.1093/emboj/18.24.6873Crossref PubMed Scopus (150) Google Scholar,11Strutt H. Strutt D. Polarity determination in the Drosophila eye.Curr. Opin. Genet. Dev. 1999; 9: 442-446https://doi.org/10.1016/S0959-437X(99)80067-7Crossref PubMed Scopus (69) Google Scholar,21Blair S.S. Eye development: Notch lends a handedness.Curr. Biol. 1999; 9: R356-R360https://doi.org/10.1016/s0960-9822(99)80226-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar During OR, as new cells join the precluster and differentiate, the precluster collectively undergoes a 90° rotation in opposing directions in the dorsal and ventral halves of the eye. This establishes the mirror-symmetric pattern most apparent in adult ommatidia across the D/V midline8Jenny A. Planar cell polarity signaling in the Drosophila eye.Curr. Top. Dev. Biol. 2010; 93: 189-227https://doi.org/10.1016/B978-0-12-385044-7.00007-2Crossref PubMed Scopus (66) Google Scholar (see also Figures 1A–1C ). In core PCP mutants, differential R3/R4 specification fails or becomes randomized and ommatidia are often misoriented,22Wolff T. Rubin G.M. Strabismus, a novel gene that regulates tissue polarity and cell fate decisions in Drosophila.Development. 1998; 125: 1149-1159Crossref PubMed Google Scholar,23Das G. Reynolds-Kenneally J. Mlodzik M. The atypical cadherin Flamingo links Frizzled and Notch signaling in planar polarity establishment in the Drosophila eye.Dev. Cell. 2002; 2: 655-666Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar,24Wu J. Klein T.J. Mlodzik M. Subcellular localization of frizzled receptors, mediated by their cytoplasmic tails, regulates signaling pathway specificity.PLoS Biol. 2004; 2: E158https://doi.org/10.1371/journal.pbio.0020158Crossref PubMed Scopus (86) Google Scholar,25Zheng L. Zhang J. Carthew R.W. Frizzled regulates mirror-symmetric pattern formation in the Drosophila eye.Development. 1995; 121: 3045-3055Crossref PubMed Google Scholar suggesting that PCP signaling not only dictates the R3/R4 cell fate specification,18Fanto M. Mlodzik M. Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye.Nature. 1999; 397: 523-526https://doi.org/10.1038/17389Crossref PubMed Scopus (185) Google Scholar,19Cooper M.T. Bray S.J. Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye.Nature. 1999; 397: 526-530https://doi.org/10.1038/17395Crossref PubMed Scopus (209) Google Scholar but also the direction and degree of OR. To date, several OR-specific regulators have been discovered on the basis of the ommatidial misorientation phenotypes associated with their mutants.26Brown K.E. Freeman M. Egfr signalling defines a protective function for ommatidial orientation in the Drosophila eye.Development. 2003; 130: 5401-5412https://doi.org/10.1242/dev.00773Crossref PubMed Scopus (53) Google Scholar,27Choi K.W. Benzer S. 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Egfr signaling regulates ommatidial rotation and cell motility in the Drosophila eye via MAPK/Pnt signaling and the Ras effector Canoe/AF6.Development. 2003; 130: 5413-5423https://doi.org/10.1242/dev.00759Crossref PubMed Scopus (66) Google Scholar,32Mirkovic I. Mlodzik M. Cooperative activities of drosophila DE-cadherin and DN-cadherin regulate the cell motility process of ommatidial rotation.Development. 2006; 133: 3283-3293https://doi.org/10.1242/dev.02468Crossref PubMed Scopus (55) Google Scholar,33Mirkovic I. Gault W.J. Rahnama M. Jenny A. Gaengel K. Bessette D. Gottardi C.J. Verheyen E.M. Mlodzik M. Nemo kinase phosphorylates beta-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-beta-catenin.Nat. Struct. Mol. Biol. 2011; 18: 665-672https://doi.org/10.1038/nsmb.2049Crossref PubMed Scopus (34) Google Scholar,34Winter C.G. Wang B. Ballew A. Royou A. Karess R. Axelrod J.D. Luo L. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton.Cell. 2001; 105: 81-91https://doi.org/10.1016/s0092-8674(01)00298-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar For example, Fz/PCP signaling feeds into cadherin-based cell adhesion machinery through downstream effectors to regulate the OR process.33Mirkovic I. Gault W.J. Rahnama M. Jenny A. Gaengel K. Bessette D. Gottardi C.J. Verheyen E.M. Mlodzik M. Nemo kinase phosphorylates beta-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-beta-catenin.Nat. Struct. Mol. Biol. 2011; 18: 665-672https://doi.org/10.1038/nsmb.2049Crossref PubMed Scopus (34) Google Scholar Furthermore, cytoskeletal reorganization of ommatidial cells is coordinated with adhesion remodeling to drive the OR process downstream of several signaling pathways, including Fz/PCP, EGFR, and Notch signaling.26Brown K.E. Freeman M. 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Farrell D.L. Zallen J.A. Abl regulates planar polarized junctional dynamics through beta-catenin tyrosine phosphorylation.Dev. Cell. 2012; 22: 309-319https://doi.org/10.1016/j.devcel.2011.12.025Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar In addition, during photoreceptor morphogenesis dAbl has been shown to be essential for the maintenance of the apicobasal integrity in photoreceptors and associated proper organization of adherens junctions.49Xiong W. Rebay I. Abelson tyrosine kinase is required for Drosophila photoreceptor morphogenesis and retinal epithelial patterning.Dev. Dyn. 2011; 240: 1745-1755https://doi.org/10.1002/dvdy.22674Crossref PubMed Scopus (7) Google Scholar Interestingly, dAbl was also shown to function within the core PCP pathway, through Dsh phosphorylation, to promote Fz/Dsh-PCP signaling within R3/R4 pairs.50Singh J. Yanfeng W.A. Grumolato L. Aaronson S.A. Mlodzik M. Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation.Genes Dev. 2010; 24: 2157-2168https://doi.org/10.1101/gad.1961010Crossref PubMed Scopus (32) Google Scholar The involvement of Abl kinases in cell adhesion and cytoskeletal remodeling has been documented in various vertebrate contexts, suggesting that many of its functions are conserved across species.36Bradley W.D. Koleske A.J. Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts.J. Cell Sci. 2009; 122: 3441-3454https://doi.org/10.1242/jcs.039859Crossref PubMed Scopus (131) Google Scholar,37Hernández S.E. Krishnaswami M. Miller A.L. Koleske A.J. How do Abl family kinases regulate cell shape and movement?.Trends Cell Biol. 2004; 14: 36-44https://doi.org/10.1016/j.tcb.2003.11.003Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar,38Wang J.Y.J. The capable ABL: what is its biological function?.Mol. Cell Biol. 2014; 34: 1188-1197https://doi.org/10.1128/MCB.01454-13Crossref PubMed Scopus (109) Google Scholar Here we show that during Drosophila eye patterning dAbl kinase negatively regulates OR downstream of the Notch receptor. Loss-of-function (LOF) and gain-of-function (GOF) genotypes of dAbl consistently cause opposite effects on the OR process. dAbl becomes apically localized in photoreceptors R8, R2/R5 and importantly R4, but not in R3, during OR. Apical junctional localization in R4 requires Notch signaling. Functionally, dAbl and Notch interact genetically during OR, and dAbl co-exists in complexes with Notch in developing eye discs. Our data collectively suggest that dAbl functions directly downstream of the Notch receptor in R4 by acting on the cadherin/β-catenin complexes and cell adhesion, via β-catenin phosphorylation. It thus serves a “brake function” during the OR process, fine-tuning OR cell motility for convergence to a 90° angle. Our past studies suggested that dAbl could have a role in the OR process (see Figures 1A and 1B for schematic of retinal development features specific to OR), as overexpression of dAbl caused OR defects, but this potential dAbl contribution to Drosophila eye patterning and morphogenesis remained unexplored.50Singh J. Yanfeng W.A. Grumolato L. Aaronson S.A. Mlodzik M. Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation.Genes Dev. 2010; 24: 2157-2168https://doi.org/10.1101/gad.1961010Crossref PubMed Scopus (32) Google Scholar To investigate how dAbl contributes to OR during retinal patterning, we analyzed the phenotypes of LOF clones of dAbl in mosaic eye tissue. Although clones of the abl2 allele can be recovered in adult eyes, they display pleiotropic developmental and morphogenetic defects (Figures 1C and 1D). Besides previously reported phenotypes of loss and malformation of photoreceptors49Xiong W. Rebay I. Abelson tyrosine kinase is required for Drosophila photoreceptor morphogenesis and retinal epithelial patterning.Dev. Dyn. 2011; 240: 1745-1755https://doi.org/10.1002/dvdy.22674Crossref PubMed Scopus (7) Google Scholar,50Singh J. Yanfeng W.A. Grumolato L. Aaronson S.A. Mlodzik M. Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation.Genes Dev. 2010; 24: 2157-2168https://doi.org/10.1101/gad.1961010Crossref PubMed Scopus (32) Google Scholar and loss of chirality,50Singh J. Yanfeng W.A. Grumolato L. Aaronson S.A. Mlodzik M. Abelson family kinases regulate Frizzled planar cell polarit" @default.
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• W4310861367 date "2022-12-01" @default.
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• W4310861367 title "Notch-dependent Abl signaling regulates cell motility during ommatidial rotation in Drosophila" @default.
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