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JOURNAL ARTICLES
Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog
A. Ruiz i Altaba
Development 1998 125: 2203-2212;

Summary

Within the developing vertebrate nervous system, it is not known how progenitor cells interpret the positional information provided by inducing signals or how the domains in which distinct groups of neural cells differentiate are defined. Gli proteins may be involved in these processes. In the frog neural plate, we have previously shown that the zinc finger transcription factor Gli1 is expressed in midline cells and mediates the effects of Shh inducing floor plate differentiation. In contrast, Gli2 and Gli3 are expressed throughout the neural plate except for the midline. Here, it is shown that Gli3 and Shh repress each other whereas Gli2, like Gli1, is a target of Shh signaling. However, only Gli1 can induce the differentiation of floor plate cells. In addition, Gli2 and Gli3 repress the ectopic induction of floor plate cells by Gli1 in co-injection assays and inhibit endogenous floor plate differentiation. The definition of the floor plate domain, therefore, appears to be defined by the antagonizing activities of Gli2 and Gli3 on Gli1 function. Because both Gli1 and Gli2 are induced by Shh, these results establish a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline. We have also previously shown that the Gli genes induce neuronal differentiation and here it is shown that there is specificity to the types of neurons the Gli proteins induce. Only Gli1 induces Nkx2.1/TTF-1(+) ventral forebrain neurons. Moreover, Gli2 and Gli3 inhibit their differentiation. In contrast, the differentiation of spinal motor neurons can be induced by the two ventrally expressed Gli genes, Gli1 and Gli2, suggesting that Gli2 directly mediates induction of motor neurons by Shh. In addition, Gli3 inhibits motor neuron differentiation by Gli2. Thus, combinatorial Gli function may pattern the neural tube, integrating positional information and cell type differentiation.

REFERENCES

    1. Buscher D.,
    2. Bosse B.,
    3. Heymer J.,
    4. Ruther U.
    (1997) Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development. Mech. Dev 62, 175–183
    OpenUrlCrossRefPubMedWeb of Science
    1. Chiang C.,
    2. Litingtung Y.,
    3. Lee E.,
    4. Young K. E.,
    5. Corden J. L.,
    6. Westphal H.,
    7. Beachy P. A.
    (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413
    OpenUrlCrossRefPubMed
    1. Dickinson M. E.,
    2. Selleck M. A. J.,
    3. McMahon A. P.,
    4. Bronner-Fraser M.
    (1995) Dorsalization of the neural tube by the non-neural ectoderm. Development 121, 2099–2106
    OpenUrlAbstract
    1. Eaton S.,
    2. Kornberg T. B.
    (1990) Repression of ci -D in posterior compartments of Drosophila by engrailed. Genes Dev 4, 1068–1077
    OpenUrlAbstract/FREE Full Text
    1. Echelard Y.,
    2. Epstein D. J.,
    3. St-Jacques B.,
    4. Shen L.,
    5. Mohler J.,
    6. McMahon J. A.,
    7. McMahon A. P.
    (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430
    OpenUrlCrossRefPubMedWeb of Science
    1. Ericson J.,
    2. Muhr J.,
    3. Placzek M.,
    4. Lints T.,
    5. Jessell T. M.,
    6. Edlund T.
    (1995) Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube. Cell 81, 747–756
    OpenUrlCrossRefPubMedWeb of Science
    1. Eriscon J.,
    2. Morton S.,
    3. Kawakami A.,
    4. Roelink H.,
    5. Jessell T. M.
    (1996) Two critical periods of Sonic hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673
    OpenUrlCrossRefPubMedWeb of Science
    1. Franz T.
    (1994) Extra-toes (Xt) homozygous mutant mice demonstrate a role of the Gli-3 gene in the development of the forebrain. Acta Anat 150, 38–44
    OpenUrlPubMedWeb of Science
    1. Harland R. M.
    (1991) In situ hybridization: an improved whole mount method for Xenopus embryos. Meth. Enzymol 36, 675–685
    OpenUrl
    1. Hata A.,
    2. Lagna G.,
    3. Massague J.,
    4. Hemmati-Brivanlou A.
    (1998) Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12, 186–197
    OpenUrlAbstract/FREE Full Text
    1. Hayashi H.,
    2. Abdollah S.,
    3. Qiu Y.,
    4. Cai J.,
    5. Xu Y.-Y.,
    6. Grinell B. W.,
    7. Richardson M. A.,
    8. Topper J.N.,
    9. Gimbrone M. A.,
    10. Wrana J. L.,
    11. Falb D.
    (1997) The MAD-related protein Smad7 associates with the TGFreceptor and functions as an antagonist of TGF signaling. Cell 89, 1165–1173
    OpenUrlCrossRefPubMedWeb of Science
    1. Hughes D. C.,
    2. Allem J.,
    3. Morley G.,
    4. Sutherland K.,
    5. Ahmed W.,
    6. Prosser J.,
    7. Lettice L.,
    8. Allan G.,
    9. Mattei M.-G.,
    10. Farrall M.,
    11. Hill R. E.
    (1997) Cloning and sequencing of the mouse Gli2 gene: localization to the Dominant hemimelia critical region. Genomics 39, 205–215
    OpenUrlCrossRefPubMedWeb of Science
    1. Hui C.-C.,
    2. Joyner A.
    (1993) A mouse model of Greig cephalopolysyndatyly syndrome: the extra-toes mutation contains an intragenic deletion of the Gli3 gene. Nature Genetics 3, 241–246
    OpenUrlCrossRefPubMedWeb of Science
    1. Hui C.-C.,
    2. Slusarski D.,
    3. Platt K. A.,
    4. Holmgren R.,
    5. Joyner A. L.
    (1994) Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm and mesoderm-derived tissues suggests multiple roles during postimplantation development. Dev. Biol 162, 402–413
    OpenUrlCrossRefPubMedWeb of Science
    1. Hynes M.,
    2. Porter J. A.,
    3. Chians C.,
    4. Chang D.,
    5. Tessier-Lavigne M.,
    6. Beachy P. A.
    (1995) Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15, 35–44
    OpenUrlCrossRefPubMedWeb of Science
    1. Hynes M.,
    2. Stone D. M.,
    3. Dowd M.,
    4. Pitts-Meek S.,
    5. Goddard A.,
    6. Gurney A.,
    7. Rosenthal A.
    (1997) Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli1. Neuron 19, 15–26
    OpenUrlCrossRefPubMedWeb of Science
    1. Imamura T.,
    2. Takese M.,
    3. Nishihara A.,
    4. Oeda E.,
    5. Hanai J.,
    6. Kawabata M.,
    7. Miyazono K.
    (1997) Smad6 inhibits signalling by the TGFsuperfamily. Nature 389, 622–626
    OpenUrlCrossRefPubMed
    1. Kang S.,
    2. Graham J. M.,
    3. Haskins Olney A.,
    4. Biesecker L. G.
    (1997) Gli3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genetics 15, 266–268
    OpenUrlCrossRefPubMedWeb of Science
    1. Kim P.,
    2. Helms A.,
    3. Johnson J.,
    4. Zimmerman K.
    (1997) XATH-1, a vertebrate homolog of Drosophila atonal, induces neuronal differentiation within ectodermal precursors. Dev. Biol 187, 1–12
    OpenUrlCrossRefPubMedWeb of Science
    1. Kinzler K. W.,
    2. Bigner S. H.,
    3. Bigner D. D.,
    4. Trent J. M.,
    5. Law M. L.,
    6. O'Brien S. J.,
    7. Wong A. J.,
    8. Vogelstein B.
    (1987) Identification of an amplified, highly expressed gene in a human glioma. Science 236, 70–73
    OpenUrlAbstract/FREE Full Text
    1. Kinzler K. W.,
    2. Vogelstein B.
    (1990) The GLI gene encodes a nuclearprotein which binds specific sequences in the human genome. Mol. Cell Biol 10, 634–642
    OpenUrlAbstract/FREE Full Text
    1. Krauss S.,
    2. Concordet J.-P.,
    3. Ingham P. W.
    (1993) A functionally conserved homolog of the Drosophila segment polarity gene hedgehog is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75, 1431–1444
    OpenUrlCrossRefPubMedWeb of Science
    1. Lazzaro A.,
    2. Price M.,
    3. De Felioce M.,
    4. Di Lauro R.
    (1991) The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the fetal brain. Development 113, 1093–1104
    OpenUrlAbstract
    1. Lee J.,
    2. Platt K. A.,
    3. Censullo P.,
    4. Ruiz i Altaba A.
    (1997) Gli1 is a target of sonic hedgehog that induces ventral neural tube development. Development 124, 2537–2552
    OpenUrlAbstract
    1. Liem K. F., Jr.,
    2. Tremml G.,
    3. Roelink H.,
    4. Jessell T. M.
    (1995) Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 82, 969–979
    OpenUrlCrossRefPubMedWeb of Science
    1. Marigo V.,
    2. Johnson R. L.,
    3. Vortkamp A.,
    4. Tabin C. J.
    (1996) Sonic hedgehogdifferentially regulates expression of Gli and Gli3 during limb development. Dev. Biol 180, 273–283
    OpenUrlCrossRefPubMedWeb of Science
    1. Marine J.-C.,
    2. Bellefroid E. J.,
    3. Pendeville H.,
    4. Martial J. A.,
    5. Pieler T.
    (1997) A role for Xenopus Gli-type zinc finger proteins in the early embryonic patterning of mesoderm and neuroectoderm. Mech Dev 63, 211–225
    OpenUrlCrossRefPubMed
    1. Martí E.,
    2. Bumcrot D. A.,
    3. Takada R.,
    4. McMahon A. P.
    (1995) Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature 375, 322–325
    OpenUrlCrossRefPubMed
    1. Masuya H.,
    2. Sagai T.,
    3. Wakana S.,
    4. Moriwaki K.,
    5. Shiroishi T. A.
    (1995) Duplicated zone of polarizing activity in polydactylous mouse mutants. Genes Dev 13, 1645–1653
    OpenUrl
    1. Mo R.,
    2. Freer A. M.,
    3. Zinyk D. L.,
    4. Crackower M. A.,
    5. Michaud J.,
    6. Heng H. H. Q.,
    7. Chik K. W.,
    8. Shi X. M.,
    9. Tsui L. C.,
    10. Cheng S. H.,
    11. Joyner A. L.,
    12. Hui C. C.
    (1997) Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124, 113–123
    OpenUrlAbstract
    1. Moury J.,
    2. Jacobson A.
    (1989) Neural fold formation in newly created boundaries between neural plate and epidermis in the axolotl. Dev. Biol 133, 44–57
    OpenUrlCrossRefPubMedWeb of Science
    1. Nakao A.,
    2. Afrakhte M.,
    3. Moren A.,
    4. Nakayama T.,
    5. Christian J.L.,
    6. Heuchel R.,
    7. Itoh S.,
    8. Kawabata M.,
    9. Heldin N.-E.,
    10. Heldin C.-H.,
    11. ten Dijke P.
    (1997) Identification of Smad7, a TGF-inducible antagonist of TGF signaling. Nature 389, 631–635
    OpenUrlCrossRefPubMed
    1. Noll E.,
    2. Miller R. H.
    (1993) Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline regions in the embryonic rat spinal cord. Development 118, 563–573
    OpenUrlAbstract
    1. Pavletich N. P.,
    2. Pabo C. O.
    (1993) Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science 261, 1701–1707
    OpenUrlAbstract/FREE Full Text
    1. Placzek M.,
    2. Jessell T.M.,
    3. Dodd J.
    (1993) Induction of floor plate differentiation by contact-dependent homeogenetic signals. Development 117, 205–218
    OpenUrlAbstract/FREE Full Text
    1. Platt K. A.,
    2. Michaud J.,
    3. Joyner A. L.
    (1997) Expression of the mouse Gli and Ptc genes is adjacent to embryonic sources of hedgehog signals suggesting a conservation of pathways between flies and mice. Development 62, 121–135
    OpenUrl
    1. Riddle R.,
    2. Johnson R. L.,
    3. Laufer E.,
    4. Tabin C.
    (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 751, 401–1418
    OpenUrl
    1. Rivera-Pomar R.,
    2. Jäckle H.
    (1996) From gradients to stripes in Drosophila embryogenesis: filling in the gaps. Trends Genet 12, 478–483
    OpenUrlCrossRefPubMedWeb of Science
    1. Roelink H.,
    2. Augsburger A.,
    3. Heemskerk J.,
    4. Korzh V.,
    5. Norlin S.,
    6. Ruiz i Altaba A.,
    7. Tanabe Y.,
    8. Placzek M.,
    9. Edlund T.,
    10. Jessell T. M.,
    11. Dodd J.
    (1994) Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76, 761–775
    OpenUrlCrossRefPubMedWeb of Science
    1. Roelink H.,
    2. Porter J. A.,
    3. Chiang C.,
    4. Tanabe Y.,
    5. Chang D. T.,
    6. Beachy P. A.,
    7. Jessell T. M.
    (1995) Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 81, 445–455
    OpenUrlCrossRefPubMedWeb of Science
    1. Ruiz i Altaba A.
    (1997) Catching a Gli-mpse of Hedgehog. Cell 90, 193–196
    OpenUrlCrossRefPubMed
    1. Ruiz i Altaba A.,
    2. Jessell T. M.,
    3. Roelink H.
    (1995) Restrictions to floor plate induction by hedgehog and winged helix genes in the neural tube of frog embryos. Mol. Cell. Neurosci 6, 106–121
    OpenUrlCrossRefPubMedWeb of Science
    1. Rupp R. A. W.,
    2. Snider L.,
    3. Weintraub H.
    (1994) Xenopus embryos regulate nuclear localization of XmyoD. Genes Dev 8, 1311–1323
    OpenUrlAbstract/FREE Full Text
    1. Ruppert J. M.,
    2. Kinzler K. W.,
    3. Wong A. J.,
    4. Bigner S. H.,
    5. Kao F. T.,
    6. Law M. L.,
    7. Seuanez H. N.,
    8. O'Brien S. J.,
    9. Vogelstein B.
    (1988) The GLI-Kruppel family of human genes. Mol. Cell. Biol 8, 3104–3113
    OpenUrlAbstract/FREE Full Text
    1. Ruppert J. M.,
    2. Vogelstein B.,
    3. Arheden K.,
    4. Kinzler K. W.
    (1990) GLI3 encodes a 190 kilodalton protein with multiple regions of GLI similarity. Mol. Cell Biol 10, 5408–5415
    OpenUrlAbstract/FREE Full Text
    1. Saha M. S.,
    2. Miles R. R.,
    3. Grainger R. M.
    (1997) Dorsal-ventral patterning during neural induction in Xenopus: Assessment of spinal cord regionalization with xHB9, a marker for the motor neuron reigion. Dev. Biol 187, 209–223
    OpenUrlCrossRefPubMedWeb of Science
    1. Sasaki H.,
    2. Hui C. C.,
    3. Nakafuku M.,
    4. Kondoh H.
    (1997) A binding site for Gli proteins is essential for HNF-3floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313–1322
    OpenUrlAbstract
    1. Tsuneizumi K.,
    2. Nakayama T.,
    3. Kamoshida Y.,
    4. Kornberg T.B.,
    5. Christian J.L.,
    6. Tabata T.
    (1997) Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389, 627–631
    OpenUrlCrossRefPubMed
    1. Turner D. L.,
    2. Weintraub H.
    (1994) Expression of achaete-scute homolog 3 in Xenopus embryos converts ectodermal cells to a neural fate. Genes Dev 8, 1434–1447
    OpenUrlAbstract/FREE Full Text
    1. Vortkamp A.,
    2. Gessler M.,
    3. Grzeschik K.-H.
    (1991) Gli3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540
    OpenUrlCrossRefPubMed
    1. Vortkamp A.,
    2. Gessler M.,
    3. Grzeschik K.-H.
    (1995) Identification of optimized target sequences for the GLI3 zinc finger protein. DNA Cell Biol 14, 629–634
    OpenUrlPubMedWeb of Science
    1. Walterhouse D.,
    2. Ahmed M.,
    3. Slusarski D.,
    4. Kalamaras J.,
    5. Boucher D.,
    6. Holmgren R.,
    7. Iannaccone P.
    (1993) gli, a zinc finger transcription factor and oncogene, is expressed during normal mouse development. Dev. Dyn 196, 91–102
    OpenUrlPubMedWeb of Science
    1. Yu W.-P.,
    2. Collarini E. J.,
    3. Pringle N. P.,
    4. Richardson W. D.
    (1994) Embryonic expression of myelin genes: evidence for a focal source of oligodendrocyte precursors in the ventricular zone of the neural tube. Neuron 12, 1353–1362
    OpenUrlCrossRefPubMedWeb of Science
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JOURNAL ARTICLES
Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog
A. Ruiz i Altaba
Development 1998 125: 2203-2212;
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