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JOURNAL ARTICLES
Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice
Q. Ding, J. Motoyama, S. Gasca, R. Mo, H. Sasaki, J. Rossant, C.C. Hui
Development 1998 125: 2533-2543;

Summary

Floor plate cells at the midline of the neural tube are specified by high-level activity of Sonic hedgehog (Shh) secreted by notochord, whereas motor neurons are thought to be specified by a lower level activity of Shh secreted in turn by floor plate cells. In Drosophila, the Gli zinc finger protein Cubitus interruptus functions as a transcription factor activating Hedgehog-responsive genes. We report that the expression of known Shh-responsive genes such as Ptc and Gli1 is downregulated in mutant mice lacking Gli2 function. Gli2 mutants fail to develop a floor plate yet still develop motor neurons, which occupy the ventral midline of the neural tube. Our results imply that Gli2 is required to mediate high level but not low level Shh activity and show that the development of motor neurons can occur in the absence of floor plate induction.

REFERENCES

    1. Akimaru H.,
    2. Chen Y.,
    3. Dai P.,
    4. Hou D.-X.,
    5. Nonaka M.,
    6. Smolik S. M.,
    7. Armstrong S.,
    8. Goodman R. H.,
    9. Ishii S.
    (1997) Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Nature 386, 735–738
    OpenUrlCrossRefPubMedWeb of Science
    1. Alexandre C.,
    2. Jacinto A.,
    3. Ingham P. W.
    (1996) Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the Cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev 10, 2003–2013
    OpenUrlAbstract/FREE Full Text
    1. Ang S.-L.,
    2. Rossant J.
    (1994) HNF-3is essential for node and notochord formation in mouse development. Cell 78, 561–574
    OpenUrlCrossRefPubMedWeb of Science
    1. Aza-Blanc P.,
    2. Ramirez-Weber F.-A.,
    3. Laget M.-P.,
    4. Schwartz C.,
    5. Kornberg T. B.
    (1997) Proteolysis that is inhibited by hedeghog targets cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043–1053
    OpenUrlCrossRefPubMedWeb of Science
    1. Burrill J.D.,
    2. Moran L.,
    3. Goulding M.D.,
    4. Saueressig H.
    (1997) PAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+interneurons that require PAX6 for their development. Development 124, 4493–4503
    OpenUrlAbstract
    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, 175–182
    OpenUrlCrossRefPubMedWeb of Science
    1. Chiang C.,
    2. Litingtung Y.,
    3. Lee E.,
    4. Young K.,
    5. Corden J. L.,
    6. Westphal H.,
    7. Beachy P.
    (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413
    OpenUrlCrossRefPubMedWeb of Science
    1. Conlon R. A.,
    2. Herrmann B. G.
    (1993) Detection of messenger RNA by in situ hybridization to postimplantation embryo whole mounts. Methods Enzymol 225, 373–383
    OpenUrlCrossRefPubMedWeb of Science
    1. Currie P. D.,
    2. Ingham P. W.
    (1996) Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish. Nature 382, 452–455
    OpenUrlCrossRefPubMed
    1. Dominguez M.,
    2. Brunner M.,
    3. Hafen E.,
    4. Basler K.
    (1996) Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitius interruptus. Science 272, 1621–1625
    OpenUrlAbstract
    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. Ekker S. C.,
    2. McGrew L. L.,
    3. Lai C.-J.,
    4. Lee J. J.,
    5. von Kessler D. P.,
    6. Moon R. T.,
    7. Beachy P. A.
    (1995) Distinct expression and shared activities of members of the hedgehog gene family of Xenopus laevis. Development 121, 2337–2347
    OpenUrlAbstract
    1. Epstein D. J.,
    2. Marti E.,
    3. Scott M. P.,
    4. McMahon A. P.
    (1996) Antagonizing cAMP-dependent protein kinase A in the dorsal CNS activates a conserved Sonic hedgehog signaling pathway. Development 122, 2885–2894
    OpenUrlAbstract
    1. Ericson J.,
    2. Morton S.,
    3. Kawakami A.,
    4. Roelink H.,
    5. Jessel 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. Ericson J.,
    2. Rashbass P.,
    3. Schedl A.,
    4. Brenner-Morton S.,
    5. Kawakami A.,
    6. van Heyningen V.,
    7. Jessell T. M.,
    8. Briscoe J.
    (1997) Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell 90, 169–180
    OpenUrlCrossRefPubMedWeb of Science
    1. Gasca S.,
    2. Hill D.,
    3. Klingensmith J.,
    4. Rossant J.
    (1995) Characterization of a gene trap insertion into a novel gene, cordon-bleu, expressed in axial structures of the gastrulating mouse embryo. Dev. Genet 17, 141–154
    OpenUrlCrossRefPubMedWeb of Science
    1. Goodrich L. V.,
    2. Johnson R. L.,
    3. Milenkovic L.,
    4. McMahon J. A.,
    5. Scott M. P.
    (1996) Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 10, 301–312
    OpenUrlAbstract/FREE Full Text
    1. Goulding M. D.,
    2. Chalepakis G.,
    3. Deutsch U.,
    4. Erselius J. R.,
    5. Gruss P.
    (1991) Pax-3, a novel murine DNA-binding protein expressed during early neurogenesis. EMBO J 10, 1135–1147
    OpenUrlPubMedWeb of Science
    1. Gratzner H. G.
    (1982) Monoclonal antibody to 5-bromo-and 5-iododeoxyuridine: a new reagent for detection of DNA replication. Science 218, 474–475
    OpenUrlAbstract/FREE Full Text
    1. Hammerschmidt M.,
    2. Brook A.,
    3. McMahon A. P.
    (1997) The world according to hedgehog. Trends in Genetics 13, 14–21
    OpenUrlCrossRefPubMedWeb of Science
    1. Hatta K.
    (1992) Role of the floor plate in axonal patterning in the zebrafish CNS. Neuron 9, 629–642
    OpenUrlCrossRefPubMedWeb of Science
    1. Hatta K.,
    2. Kimmel C.,
    3. Ho R.,
    4. Walker C.
    (1991) The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350, 339–341
    OpenUrlCrossRefPubMed
    1. Hepker J.,
    2. Wang Q.-T.,
    3. Motzny C. K.,
    4. Holmgren R.,
    5. Orenic T. V.
    (1997) Drosophilacubitus interruptus forms a negative feedback loop with patched and regulates expression of Hedgehog target genes. Development 124, 549–558
    OpenUrlAbstract
    1. Hui C.-c.,
    2. Joyner A. L.
    (1993) A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toesJmutation contains an intragenic deletion of the Gli3 gene. Nature Genet 3, 241–246
    OpenUrlCrossRefPubMedWeb of Science
    1. Hui C.-c.,
    2. Slusarski D.,
    3. Platt K.,
    4. Holmgren R.,
    5. Joyner A.
    (1994) Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli2, and Gli3, 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. Chiang C.,
    4. Chang D.,
    5. Tessier-Lavigne M.,
    6. Beachy P.,
    7. Rosenthal 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 Gli-1. Neuron 19, 15–26
    OpenUrlCrossRefPubMedWeb of Science
    1. Kang S.,
    2. Graham J. M.,
    3. Olney A. H.,
    4. Biesecker L. G.
    (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genet 15, 266–268
    OpenUrlCrossRefPubMedWeb of Science
    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.,
    2. Tremml G.,
    3. Jessell T.M.
    (1997) A role for the roof plate and its resident TGF-related proteins in neuronal patterning in the dorsal spinal cord. Cell 91, 127–138
    OpenUrlCrossRefPubMedWeb of Science
    1. Marigo V.,
    2. Johnson R. L.,
    3. Vortkamp A.,
    4. Tabin C. J.
    (1996) Sonic hedgehog differentially 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 earlyembryonic patterning of mesoderm and neuroectoderm. Mech. Dev 63, 211–225
    OpenUrlCrossRefPubMedWeb of Science
    1. Marti E.,
    2. Bumcrot D.,
    3. Takada R.,
    4. McMahon A.
    (1995) Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature 375, 322–325
    OpenUrlCrossRefPubMed
    1. Marti E.,
    2. Takada R.,
    3. Bumcrot D.,
    4. Sasaki H.,
    5. McMahon A.
    (1995) Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo. Development 121, 2537–2547
    OpenUrlAbstract
    1. Masuya H.,
    2. Sagai T.,
    3. Moriwaki K.,
    4. Shiroishi T.
    (1997) Multigenic control of the localization of the zone of polarizing activity in limb morphogenesis in the mouse. Dev. Biol 182, 42–51
    OpenUrlCrossRefPubMedWeb of Science
    1. Mo R.,
    2. Freer A. M.,
    3. Zinyk D.,
    4. Crackower M. A.,
    5. Heng H. H.-Q.,
    6. Chik K. W.,
    7. Shi X.-M.,
    8. Tsui L.-C.,
    9. Cheng S. H.,
    10. Joyner A. L.,
    11. Hui C.-c.
    (1997) Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal development. Development 124, 113–123
    OpenUrlAbstract
    1. Osumi N.,
    2. Hirota A.,
    3. Ohuchi H.,
    4. Nakafuku M.,
    5. Iimura T.,
    6. Kuratani S.,
    7. Fujiwara M.,
    8. Noji S.,
    9. Eto K.
    (1997) Pax-6 is involved in the specification of hindbrain motor neuron subtype. Development 124, 2961–2972
    OpenUrlAbstract
    1. Perrimon N.
    (1995) Hedgehog and beyond. Cell 80, 517–520
    OpenUrlCrossRefPubMedWeb of Science
    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. Mech. Dev 62, 121–135
    OpenUrlCrossRefPubMedWeb of Science
    1. Radhakrishna U.,
    2. Wild A.,
    3. Grzeschil K.-H.,
    4. Antonaraskis S. E.
    (1997) Mutation in GLI3 in postaxial polydactyly type A. Nature Genetics 17, 269–271
    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.
    (1996) Coexpression of HNF-3and Isl-1/2 and mixed distribution of ventral cell types in the early neural tube. Int. J. Dev. Biol 40, 1081–1088
    OpenUrlPubMedWeb of Science
    1. Ruiz i Altaba A.
    (1997) Catching a Gli-mpse of Hedgehog. Cell 90, 193–196
    OpenUrlCrossRefPubMedWeb of Science
    1. Ruiz i Altaba A.,
    2. Cox C.,
    3. Jessell T. M.,
    4. Klar A.
    (1993) Ectopic neural expression of a floor plate marker in frog embryos injected with the midline transcription factor Pintallavis. Proc. Natl. Acad. Sci. USA 90, 8268–8272
    OpenUrlAbstract/FREE Full Text
    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. Molec. Cell. Neurosci 6, 106–121
    OpenUrlCrossRefPubMedWeb of Science
    1. Ruiz i Altaba A.,
    2. Placzek M.,
    3. Baldassare M.,
    4. Dodd J.,
    5. Jessel T. M.
    (1995) Early stages of notochord and floor plate development in the chick embryo defined by normal and induced expression of HNF3. Dev. Biol 170, 299–313
    OpenUrlCrossRefPubMedWeb of Science
    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, 3104–3133
    OpenUrlAbstract/FREE Full Text
    1. Ruppert J. M.,
    2. Vogelstein B.,
    3. Kinzler K. W.
    (1991) The zinc finger protein GLI transform primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol 11, 1724–1728
    OpenUrlAbstract/FREE Full Text
    1. Sasaki H.,
    2. Hogan B. L. M.
    (1994) HNF-3as a regulator of floor plate development. Cell 76, 103–115
    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-3 floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313–1322
    OpenUrlAbstract
    1. Schaeren-Wiemers N.,
    2. Gerfin-Moser A.
    (1993) A single protocol to detect transcripts of various types and expression levels in neural tissues and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440
    OpenUrlCrossRefPubMedWeb of Science
    1. Schimmang T.,
    2. Lemaistre M.,
    3. Vortkamp A.,
    4. Ruther U.
    (1992) Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt). Development 116, 799–804
    OpenUrlAbstract
    1. Shimamura K.,
    2. Hartigan D. J.,
    3. Martinez S.,
    4. Puelles L.,
    5. Rubenstein J.L.R.
    (1995) Longitudinal organization of the anterior neural plate and neural tube. Development 121, 3923–3933
    OpenUrlAbstract
    1. Tanabe Y.,
    2. Jessell T. M.
    (1996) Diversity and pattern in the developing spinal cord. Science 274, 1115–1123
    OpenUrlAbstract/FREE Full Text
    1. Tanabe Y.,
    2. Roelink H.,
    3. Jessell T.
    (1995) Induction of motor neurons by Sonic hedgehog is independent of floor plate differentiation. Current Biology 5, 651–658
    OpenUrlCrossRefPubMedWeb of Science
    1. Tremblay P.,
    2. Pituello F.,
    3. Gruss P.
    (1996) Inhibition of floor plate differentiation by Pax3: evidence from ectopic expression in transgenic mice. Development 122, 2555–2567
    OpenUrlAbstract
    1. Tsuchida T.,
    2. Ensini M.,
    3. Morton S. B.,
    4. Baldassare M.,
    5. Edlund T.,
    6. Jessell T. M.,
    7. Pfaff S. L.
    (1994) Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79, 957–970
    OpenUrlCrossRefPubMedWeb of Science
    1. van Straaten H. W. M.,
    2. Hekking J. W. M.,
    3. Beursgens J. P. W. M.,
    4. Terwindt-Rouwenhorst E.,
    5. Drukker J.
    (1989) Effect of the notochord on proliferation and differentiation in the neural tube of the chick embryo. Development 107, 793–803
    OpenUrlAbstract/FREE Full Text
    1. von Ohlen T.,
    2. Lessing D.,
    3. Nusse R.,
    4. Hooper J. E.
    (1997) Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein. Proc. Natl. Acad. Sci. USA 94, 2404–2409
    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
    OpenUrlCrossRefPubMedWeb of Science
    1. Walter C.,
    2. Gruss P.
    (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113, 1435–1450
    OpenUrlAbstract
    1. Walterhouse D.,
    2. Ahmed M.,
    3. Slusarski D.,
    4. Kalamaras J.,
    5. Boucher D.,
    6. Holmgren R.,
    7. Iannaccone P.
    (1993) gli, aputative zinc finger transcription factor, is expressed in a segmental pattern during normal mouse development. Dev. Dyn 196, 91–102
    OpenUrlPubMedWeb of Science
    1. Weinstein D.,
    2. Ruiz i Altaba A.,
    3. Chen W.,
    4. Hoodless P.,
    5. Prezioso V.,
    6. Jessell T.,
    7. Darnell J.
    (1994) The winged-helix transcription factor HNF-3is required for notochord development in the mouse embryo. Cell 78, 575–688
    OpenUrlCrossRefPubMedWeb of Science
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JOURNAL ARTICLES
Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice
Q. Ding, J. Motoyama, S. Gasca, R. Mo, H. Sasaki, J. Rossant, C.C. Hui
Development 1998 125: 2533-2543;
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