title: Ras/MEK/MAPK-mediated regulation of heparin sulphate proteoglycans promotes retinal fate in the Drosophila eye-antennal disc.
abstract: Generating cellular heterogeneity is crucial to the development of complex organs. Organ-fate selector genes and signalling pathways generate cellular diversity by subdividing and patterning naïve tissues to assign them regional identities. The Drosophila eye-antennal imaginal disc is a well-characterised system in which to study regional specification; it is first divided into antennal and eye fates and subsequently retinal differentiation occurs within only the eye field. During development, signalling pathways and selector genes compete with and mutually antagonise each other to subdivide the tissue. Wingless (Wg) signalling is the main inhibitor of retinal differentiation; it does so by promoting antennal/head-fate via selector factors and by antagonising Hedgehog (Hh), the principal differentiation-initiating signal. Wg signalling must be suppressed by JAK/STAT at the disc posterior in order to initiate retinal differentiation. Ras/MEK/MAPK signalling has also been implicated in initiating retinal differentiation but its mode of action is not known. We find that compromising Ras/MEK/MAPK signalling in the early larval disc results in expanded antennal/head cuticle at the expense of the compound eye. These phenotypes correspond both to perturbations in selector factor expression, and to de-repressed wg. Indeed, STAT activity is reduced due to decreased mobility of the ligand Unpaired (Upd) along with a corresponding loss in Dally-like protein (Dlp), a heparan sulphate proteoglycan (HSPG) that aids Upd diffusion. Strikingly, blocking HSPG biogenesis phenocopies compromised Ras/MEK/MAPK, while restoring HSPG expression rescues the adult phenotype significantly. This study identifies a novel mode by which the Ras/MEK/MAPK pathway regulates regional-fate specification via HSPGs during development.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
authors.forename: Vilaiwan M
authors.initials: VM
authors.lastname: Fernandes
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
authors.forename: Tirthadipa
authors.initials: T
authors.lastname: Pradhan-Sundd
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Blaquiere
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6. Electronic address: everheye@sfu.ca.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Verheyen
mesh_terms: D000818:Animals; D019070:Cell Lineage; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry*; D007814:Larva / Q000378:metabolism; D008024:Ligands; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D034622:RNA Interference; D012160:Retina / Q000196:embryology*; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; D011494:Protein Kinases; C119848:Dsor1 protein, Drosophila; D048369:MAP Kinase Kinase 1; D018631:ras Proteins
keywords: JAK/STAT; Ras/MEK/MAPK; Regional-fate; Selector factors; Unpaired; Wingless