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JOURNAL ARTICLES
Pax6 induces ectopic eyes in a vertebrate
R.L. Chow, C.R. Altmann, R.A. Lang, A. Hemmati-Brivanlou
Development 1999 126: 4213-4222;

Summary

We report here that misexpression of the transcription factor Pax6 in the vertebrate Xenopus laevis leads to the formation of differentiated ectopic eyes. Multiple molecular markers indicated the presence of mature lens fiber cells, ganglion cells, Muller cells, photoreceptors and retinal pigment epithelial cells in a spatial arrangement similar to that of endogenous eyes. Lineage tracing experiments showed that lens, retina and retinal pigment epithelium arose as a consequence of the cell-autonomous function of Pax6. These experiments also reveal that the cell autonomous activity of misexpressed Pax6 causes the ectopic expression of a number of genes including Rx, Otx2, Six3 and endogenous Pax6, each of which has been implicated in eye development. The formation of ectopic and endogenous eyes could be suppressed by coexpression of a dominant-negative form of Pax6. These data show that in vertebrates, as in the invertebrate Drosophila melanogaster, Pax6 is both necessary and sufficient to trigger the cascade of events required for eye formation.

Reference

    1. Acampora D.,
    2. Mazan S.,
    3. Lallemand Y.,
    4. Avantaggiato V.,
    5. Maury M.,
    6. Simeone A.,
    7. Brulet P.
    (1995) Forebrain and midbrain regions are deleted in Otx2mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 121, 3279–3290
    OpenUrlAbstract
    1. Adelmann
    (1936) The Problem of Cyclopia, Pt. I. Quar. Rev. Biol 11, 161–182
    OpenUrlCrossRef
    1. Adelmann H. B.
    (1929) Experimental studies on the development of the eye. II. The eye-forming potencies of the median portions of the urodelean neural plate (Triton taeniatus and Amblystoma punctatum). J. Exp. Zool 54, 219–317
    OpenUrl
    1. Altmann C. R.,
    2. Chow R. L.,
    3. Lang R. A.,
    4. Hemmati-Brivanlou A.
    (1997) Lens induction by Pax-6 in Xenopus laevis. Dev. Biol 185, 119–123
    OpenUrlCrossRefPubMedWeb of Science
    1. Andreazzoli M.,
    2. Gestri G.,
    3. Angeloni D.,
    4. Menna E.,
    5. Barsacchi G.
    (1999) Role of xrx1 in Xenopus eye and anterior brain development. Development 126, 2451–2460
    OpenUrlAbstract
    1. Callaerts P.,
    2. Halder G.,
    3. Gehring W. J.
    (1997) PAX-6 in development and evolution. Annu. Rev. Neurosci 20, 483–532
    OpenUrlCrossRefPubMedWeb of Science
    1. Casarosa S.,
    2. Andreazzoli M.,
    3. Simeone A.,
    4. Barsacchi G.
    (1997) Xrx1, a novel Xenopus homeobox gene expressed during eye and pineal gland development. Mech. Dev 61, 187–198
    OpenUrlCrossRefPubMedWeb of Science
    1. Chen R.,
    2. Amoui M.,
    3. Zhang Z.,
    4. Mardon G.
    (1997) Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila. Cell 91, 893–903
    OpenUrlCrossRefPubMedWeb of Science
    1. Cuny R.,
    2. Malacinski G. M.
    (1986) Axolotl retina and lens development: mutual tissue stimulation and autonomous failure in the eyeless mutant retina. J. Embryol. Exp. Morph 96, 151–170
    OpenUrlPubMed
    1. Czerny T.,
    2. Halder G.,
    3. Kloter U.,
    4. Souabni A.,
    5. Gehring W. J.,
    6. Busslinger M.
    (1999) twin of eyeless, a second Pax-6 gene of Drosophila, acts upstream of eyeless in the control of eye development. Mol Cell 3, 297–307
    OpenUrl
    1. Ekker S. C.,
    2. Ungar A. R.,
    3. Greenstein P.,
    4. von Kessler D. P.,
    5. Porter J. A.,
    6. Moon R. T.,
    7. Beachy P. A.
    (1995) Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Curr. Biol 5, 944–955
    OpenUrlCrossRefPubMedWeb of Science
    1. Fujiwara M.,
    2. Uchida T.,
    3. Osumi-Yamashita N.,
    4. Eto K.
    (1994) Uchida rat (rSey): a new mutant rat with craniofacial abnormalities resembling those of the mouse Sey mutant. Differentiation 57, 31–38
    OpenUrlCrossRefPubMedWeb of Science
    1. Glaser T.,
    2. Lane J.,
    3. Housman D.
    (1990) A mouse model of the aniridia-Wilms tumor deletion syndrome. Science 250, 823–827
    OpenUrlAbstract/FREE Full Text
    1. Glaser T.,
    2. Walton D. S.,
    3. Maas R. L.
    (1992) Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat. Genet 2, 232–239
    OpenUrlCrossRefPubMedWeb of Science
    1. Halder G.,
    2. Callaerts P.,
    3. Flister S.,
    4. Walldorf U.,
    5. Kloter U.,
    6. Gehring W. J.
    (1998) Eyeless initiates the expression of both sine oculis and eyes absent during Drosophila compound eye development. Development 125, 2181–2191
    OpenUrlAbstract
    1. Halder G.,
    2. Callaerts P.,
    3. Gehring W. J.
    (1995) Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267, 1788–1792
    OpenUrlAbstract/FREE Full Text
    1. Hemmati-Brivanlou A.,
    2. de la Torre J. R.,
    3. Holt C.,
    4. Harland R. M.
    (1991) Cephalic expression and molecular characterization of Xenopus En-2. Development 111, 715–724
    OpenUrlAbstract
    1. Hemmati-Brivanlou A.,
    2. Kelly O. G.,
    3. Melton D. A.
    (1994) Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 77, 283–295
    OpenUrlCrossRefPubMedWeb of Science
    1. Hemmati-Brivanlou A.,
    2. Melton D. A.
    (1994) Inhibition of activin receptor signaling promotes neuralization in Xenopus. Cell 77, 273–281
    OpenUrlCrossRefPubMedWeb of Science
    1. Hicks D.,
    2. Molday R. S.
    (1985) Differential immunogolddextranlabelling of bovine and frog rod and cone cells using monoclonal antibodies against bovine rhodopsin. Exp. Eye Res 42, 55–71
    1. Hill R. E.,
    2. Favor J.,
    3. Hogan B. L.,
    4. Ton C. C.,
    5. Saunders G. F.,
    6. Hanson I. M.,
    7. Prosser J.,
    8. Jordan T.,
    9. Hastie N. D.,
    10. van Heyningen V.
    (1991) Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature 354, 522–525
    OpenUrlCrossRefPubMedWeb of Science
    1. Hirsch N.,
    2. Harris W. A.
    (1997) Xenopus Pax-6 and retinal development. J. Neurobiol 32, 45–61
    OpenUrlCrossRefPubMedWeb of Science
    1. Hogan B. L.,
    2. Horsburgh G.,
    3. Cohen J.,
    4. Hetherington C. M.,
    5. Fisher G.,
    6. Lyon M. F.
    (1986) Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse. J. Embryol. Exp. Morphol 97, 95–110
    OpenUrlPubMedWeb of Science
    1. Jacobson A. G.
    (1958) The roles of neural and nonneural tissues in lens induction. J. Exp. Zool 139, 525–557
    OpenUrlCrossRefWeb of Science
    1. Jordan T.,
    2. Hanson I.,
    3. Zaletayev D.,
    4. Hodgson S.,
    5. Prosser J.,
    6. Seawright A.,
    7. Hastie N.,
    8. van Heyningen V.
    (1992) The human PAX6 gene is mutated in two patients with aniridia. Nat. Genet 1, 328–332
    OpenUrlCrossRefPubMedWeb of Science
    1. Keller R. E.
    (1976) Vital dye mapping of the gastrula and neurula of Xenopus laevis. II. Prospective areas and morphogenetic movements of the deep layer. Dev. Biol 51, 118–137
    OpenUrlCrossRefPubMedWeb of Science
    1. Lamb T. M.,
    2. Harland R. M.
    (1995) Fibroblast growth factor is a direct neural inducer, which combined with noggin generates anterior-posterior neural pattern. Development 121, 3627–3636
    OpenUrlAbstract
    1. Li H.,
    2. Tierney C.,
    3. Wen L.,
    4. Wu J. Y.,
    5. Rao Y.
    (1997) A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate. Development 124, 603–615
    OpenUrlAbstract
    1. Loosli F.,
    2. Koster R. W.,
    3. Carl M.,
    4. Krone A.,
    5. Wittbrodt J.
    (1998) Six3, a medaka homologue of the Drosophila homeobox gene sine oculis is expressed in the anterior embryonic shield and the developing eye. Mech. Dev 74, 159–164
    OpenUrlCrossRefPubMedWeb of Science
    1. Loosli F.,
    2. Winkler S.,
    3. Wittbrodt J.
    (1999) Six3 overexpression initiates the formation of ectopic retina. Genes Dev 13, 649–654
    OpenUrlAbstract/FREE Full Text
    1. Macdonald R.,
    2. Barth K. A.,
    3. Xu Q.,
    4. Holder N.,
    5. Mikkola I.,
    6. Wilson S. W.
    (1995) Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121, 3267–3278
    OpenUrlAbstract
    1. Mangold O.
    (1928) Das determinationsproblem. I. Das nervensystem und die sinnesorgane der seitenlinie unter spezieller Beruchschtigung der amphibien. Ergebn. Biol 3, 152–227
    OpenUrl
    1. Mathers P. H.,
    2. Grinberg A.,
    3. Mahon K. A.,
    4. Jamrich M.
    (1997) The Rx homeobox gene is essential for vertebrate eye development. Nature 387, 603–607
    OpenUrlCrossRefPubMedWeb of Science
    1. Matsuo I.,
    2. Kuratani S.,
    3. Kimura C.,
    4. Takeda N.,
    5. Aizawa S.
    (1995) Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev 9, 2646–2658
    OpenUrlAbstract/FREE Full Text
    1. Oliver G.,
    2. Loosli F.,
    3. Koester R.,
    4. Wittbrodt J.,
    5. Gruss P.
    (1996) Ectopic lens induction in fish in response to the murine homeobox gene Six3. Mech. Dev 60, 233–239
    OpenUrlCrossRefPubMedWeb of Science
    1. Oliver G.,
    2. Mailhos A.,
    3. Wehr R.,
    4. Copeland N. G.,
    5. Jenkins N. A.,
    6. Gruss P.
    (1995) Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055
    OpenUrlAbstract
    1. Pannese M.,
    2. Polo C.,
    3. Andreazzoli M.,
    4. Vignali R.,
    5. Kablar B.,
    6. Barsacchi G.,
    7. Boncinelli E.
    (1995) The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions. Development 121, 707–720
    OpenUrlAbstract
    1. Piatigorsky J.,
    2. Nickerson J. M.,
    3. King C. R.,
    4. Inana G.,
    5. Hejtmancik J. F.,
    6. Hawkins J. W.,
    7. Borras T.,
    8. Shinohara T.,
    9. Wistow G.,
    10. Norman B.
    (1984) Crystallin genes: templates for lens transparency. Ciba Found. Symp 106, 191–207
    OpenUrlPubMed
    1. Pignoni F.,
    2. Hu B.,
    3. Zavitz K. H.,
    4. Xiao J.,
    5. Garrity P. A.,
    6. Zipursky S. L.
    (1997) The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91, 881–891
    OpenUrlCrossRefPubMedWeb of Science
    1. Quinn J. C.,
    2. West J. D.,
    3. Hill R. E.
    (1996) Multiple functions for Pax6 in mouse eye and nasal development. Genes Dev 10, 435–446
    OpenUrlAbstract/FREE Full Text
    1. Quiring R.,
    2. Walldorf U.,
    3. Kloter U.,
    4. Gehring W. J.
    (1994) Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 265, 785–789
    OpenUrlAbstract/FREE Full Text
    1. Sakaguchi D. S.,
    2. Janick L. M.,
    3. Reh T. A.
    (1997) Basic fibroblast growth factor (FGF-2) induced transdifferentiation of retinal pigment epithelium: generation of retinal neurons and glia. Dev. Dyn 209, 387–398
    OpenUrlCrossRefPubMedWeb of Science
    1. Schedl A.,
    2. Ross A.,
    3. Lee M.,
    4. Engelkamp D.,
    5. Rashbass P.,
    6. van Heyningen V.,
    7. Hastie N. D.
    (1996) Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell 86, 71–82
    OpenUrlCrossRefPubMedWeb of Science
    1. Singh S.,
    2. Tang H. K.,
    3. Lee J. Y.,
    4. Saunders G. F.
    (1998) Truncation mutations in the transactivation region of PAX6 result in dominant-negative mutants. J. Biol. Chem 273, 21531–21541
    OpenUrlAbstract/FREE Full Text
    1. Smith W. C.,
    2. Harland R. M.
    (1991) Injected Xwnt-8 RNA acts early in Xenopus embryos to promote formation of a vegetal dorsalizing center. Cell 67, 753–765
    OpenUrlCrossRefPubMedWeb of Science
    1. St-Onge L.,
    2. Sosa-Pineda B.,
    3. Chowdhury K.,
    4. Mansouri A.,
    5. Gruss P.
    (1997) Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 387, 406–409
    OpenUrlCrossRefPubMed
    1. Tang H. K.,
    2. Singh S.,
    3. Saunders G. F.
    (1998) Dissection of the transactivation function of the transcription factor encoded by the eye developmental gene PAX6. J. Biol. Chem 273, 7210–7221
    OpenUrlAbstract/FREE Full Text
    1. Torres M.,
    2. Gomez-Pardo E.,
    3. Gruss P.
    (1996) Pax2 contributes to inner ear patterning and optic nerve trajectory. Development 122, 3381–3391
    OpenUrlAbstract
    1. Vardimon L.,
    2. Fox L. E.,
    3. Cohen-Kupiec R.,
    4. Degenstein L.,
    5. Moscona A. A.
    (1991) Expression of v-src in embryonic neural retina alters cell adhesion, inhibits histogenesis, and prevents induction of glutamine synthetase. Mol. Cell Biol 11, 5275–5284
    OpenUrlAbstract/FREE Full Text
    1. Vize P. D.,
    2. Melton D. A.,
    3. Hemmati-Brivanlou A.,
    4. Harland R. M.
    (1991) Assays for gene function in developing Xenopus embryos. Methods Cell Biol 36, 367–387
    OpenUrlPubMed
    1. Walther C.,
    2. Gruss P.
    (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113, 1435–1449
    OpenUrlAbstract
    1. Wetts R.,
    2. Fraser S. E.
    (1988) Multipotent precursors can give rise to all major cell types of the frog retina. Science 239, 1142–1145
    OpenUrlAbstract/FREE Full Text
    1. Zigler J. S.,
    2. Sidbury J. B. Jr
    (1976) A comparative study of beta-crystallin from six mammals. Comp. Biochem. Physiol. [B] 53, 349–355
    OpenUrlCrossRefPubMed
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JOURNAL ARTICLES
Pax6 induces ectopic eyes in a vertebrate
R.L. Chow, C.R. Altmann, R.A. Lang, A. Hemmati-Brivanlou
Development 1999 126: 4213-4222;
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