Advertisement
JOURNAL ARTICLES
Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development
R. Mo, A.M. Freer, D.L. Zinyk, M.A. Crackower, J. Michaud, H.H. Heng, K.W. Chik, X.M. Shi, L.C. Tsui, S.H. Cheng, A.L. Joyner, C. Hui
Development 1997 124: 113-123;

Summary

The correct patterning of vertebrate skeletal elements is controlled by inductive interactions. Two vertebrate hedgehog proteins, Sonic hedgehog and Indian hedgehog, have been implicated in skeletal development. During somite differentiation and limb development, Sonic hedgehog functions as an inductive signal from the notochord, floor plate and zone of polarizing activity. Later in skeletogenesis, Indian hedgehog functions as a regulator of chondrogenesis during endochondral ossification. The vertebrate Gli zinc finger proteins are putative transcription factors that respond to Hedgehog signaling. In Drosophila, the Gli homolog cubitus interruptus is required for the activation of hedgehog targets and also functions as a repressor of hedgehog expression. We show here that Gli2 mutant mice exhibit severe skeletal abnormalities including cleft palate, tooth defects, absence of vertebral body and intervertebral discs, and shortened limbs and sternum. Interestingly, Gli2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241–246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives. Although Gli2 and Gli3 are not functionally equivalent, double mutant analysis indicates that, in addition to their specific roles, they also serve redundant functions during skeletal development. The role of Gli2 and Gli3 in Hedgehog signaling during skeletal development is discussed.

REFERENCES

    1. Bitgood M. J.,
    2. McMahon A. P.
    (1995) Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol 172, 126–138
    OpenUrlCrossRefPubMedWeb of Science
    1. Chang D. T.,
    2. et al.
    (1994) Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120, 3339–3353
    OpenUrlAbstract
    1. Christ B.,
    2. Ordahl C.
    (1995) Early stages of chick somite development. Anat. Embryol 191, 381–396
    OpenUrlCrossRefPubMed
    1. Cohn M. J.,
    2. Tickle C.
    (1996) Limbs: a model for pattern formation within the vertebrate body plan. Trends Genet 12, 253–257
    OpenUrlCrossRefPubMedWeb of Science
    1. Davis A. P.,
    2. Capecchi M. R.
    (1996) A mutational analysis of the 5 HoxD genes: dissection of genetic interactions during limb development in the mouse. Development 122, 1175–1185
    OpenUrlAbstract
    1. Dietrich S.,
    2. Schubert F. R.,
    3. Gruss P.
    (1993) Altered Pax gene expression in murine notochord mutants: The notochord is required to initiate and maintain ventral identity in the somite. Mech. Dev 44, 189–207
    OpenUrlCrossRefPubMedWeb of Science
    1. Dietrich S.,
    2. Gruss P.
    (1995) undulated phenotypes suggest a role of Pax-1 for the development of vertebral and extravertebral structures. Dev. Biol 167, 529–548
    OpenUrlCrossRefPubMedWeb of Science
    1. Dolle P.,
    2. Izpisua-Belmonte J.-C.,
    3. Falkenstein H.,
    4. Renucci A.,
    5. Duboule D.
    (1989) Coordinate expression of the murine Hox-5 complex homeobox-containing genes during limb pattern formation. Nature 342, 767–772
    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 cubitus interruptus. Science 272, 1621–1625
    OpenUrlAbstract
    1. Echelard Y.,
    2. Epstein D. J.,
    3. St.-Jauques B.,
    4. Shen L.,
    5. Mohler J. A.,
    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. Erlebacher A.,
    2. Filvaroff E.,
    3. Gitelman S.,
    4. Derynck R.
    (1995) Toward a molecular understanding of skeletal development. Cell 80, 371–378
    OpenUrlCrossRefPubMedWeb of Science
    1. Fan C.-M.,
    2. Tessier-Lavigne M.
    (1994) Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog. Cell 79, 1175–1186
    OpenUrlCrossRefPubMedWeb of Science
    1. Fan C.-M.,
    2. Porter J. A.,
    3. Chiang C.,
    4. Chang D. T.,
    5. Beachy P.,
    6. Tessier-Lavigne M.
    (1995) Long-range sclerotome induction by Sonic Hedgehog: direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway. Cell 81, 457–465
    OpenUrlCrossRefPubMedWeb of Science
    1. Franz T.
    (1994) Extra-toes (Xt) homozygous mutant mice demonstrate a role for the Gli-3 gene in the development of the forebrain. Acta Anat 150, 38–44
    OpenUrlPubMedWeb of Science
    1. Fromental-Ramain C.,
    2. Warot X.,
    3. Lakkaraju S.,
    4. Favier B.,
    5. Haack H.,
    6. Birling C.,
    7. Dierich A.,
    8. Dolle P.,
    9. Chambon P.
    (1996) Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development 122, 461–472
    OpenUrlAbstract
    1. Gollop T. R.,
    2. Fontes L.R.
    (1985) The Greig cephalopolysyndactyly syndrome: Report of a family and review of the literature. Am. J. Med. Genet 22, 59–68
    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. Haack H.,
    2. Gruss P.
    (1993) The establishment of murine Hox-1 expression domains during patterning of the limb. Dev. Biol 157, 410–422
    OpenUrlCrossRefPubMedWeb of Science
    1. Hahn H.,
    2. et al.
    (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851
    OpenUrlCrossRefPubMedWeb of Science
    1. Hammerschmidt M.,
    2. Bitgood M. J.,
    3. McMahon A. P.
    (1996) Protein kinase A is a common negative regulator of Hedgehog signaling in the vertebrate embryo. Genes Dev 10, 647–658
    OpenUrlAbstract/FREE Full Text
    1. Hogan B. L. M.
    (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10, 1580–1594
    OpenUrlFREE Full Text
    1. Hui C.-c.,
    2. Joyner A. L.
    (1993) A mouse model of Greigcephalopolysyndactyly syndrome: the extra-toesJ mutation 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. 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. Chiang C.,
    4. Chang D.,
    5. Tessier-Lavigne,
    6. Beachy P. A.,
    7. Rosenthal A.
    (1995) Induction of midbrain dopaminergic neurons by Sonic Hedgehog. Neuron 15, 35–44
    OpenUrlCrossRefPubMedWeb of Science
    1. Iseki S.,
    2. Araga A.,
    3. Ohuchi H.,
    4. Nohno T.,
    5. Yoshioka H.,
    6. Hayashi F.,
    7. Noji S.
    (1996) Sonic hedgehog is expressed in epithelial cells during development of whsiker, hair, and tooth. Biochem. Biophys. Res. Comm 218, 688–693
    OpenUrlCrossRefPubMedWeb of Science
    1. Jegalian B. G.,
    2. De Robertis E. M.
    (1992). Homeotic transformations in the mouse induced by overexpression of a human Hox3.3 transgene. Cell 71, 901–910
    OpenUrlCrossRefPubMedWeb of Science
    1. Johnson D. R.
    (1967) Extra-toes: a new mutant gene causing multiple abnormalities in the mouse. J. Embryol. Exp. Morph 17, 543–581
    OpenUrlPubMedWeb of Science
    1. Johnson R. L.,
    2. Laufer E.,
    3. Riddle R. D.,
    4. Tabin C.
    (1994) Ectopic expression of Sonic hedgehog alters dorsal-ventral patterning of somites. Cell 79, 1165–1173
    OpenUrlCrossRefPubMedWeb of Science
    1. Johnson R. L.,
    2. Grenier J.,
    3. Scott M. P.
    (1995) Patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. Development 121, 4161–4170
    OpenUrlAbstract
    1. Johnson R. L.,
    2. et al.
    (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671
    OpenUrlAbstract
    1. Koseki H.,
    2. Wallin J.,
    3. Wilting J.,
    4. Mizutani Y.,
    5. Ebensperger C.,
    6. Christ B.,
    7. Balling R.
    (1993) Pax1 as a mediator of notochordal signals in the dorsoventral specification of vertebrae. Development 119, 649–660
    OpenUrlAbstract/FREE Full Text
    1. Koyama E.,
    2. et al.
    (1996) Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse. Dev Dyn 206, 59–72
    OpenUrlCrossRefPubMedWeb of Science
    1. Lanske B.,
    2. et al.
    (1996) PTH/PTHrP receptor in early development and Indian Hedgehog-regulated bone growth. Science 273, 663–666
    OpenUrlAbstract
    1. Laufer E.,
    2. Nelson C. E.,
    3. Johnson R. L.,
    4. Morgan B. A.,
    5. Tabin C.
    (1994) Sonic hedgehog and FGF-4 act througha signaling cascade and feedback loop to integrate growth and patterning on the developing limb. Cell 79, 993–1003
    OpenUrlCrossRefPubMedWeb of Science
    1. Lufkin T.,
    2. Mark M.,
    3. Hart C. P.,
    4. Dolle P.,
    5. LeMeur M.,
    6. Chambon P.
    (1992) Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature 359, 835–841
    OpenUrlCrossRefPubMed
    1. Margio V.,
    2. Scott M. P.,
    3. Johnson R. L.,
    4. Goodrich L. V.,
    5. Tabin C. J.
    (1996) Conservation in hedgehog signaling: induction of a chicken patched homolog by Sonic hedgehog in the developing limb. Development 122, 1225–1233
    OpenUrlAbstract
    1. Martin J. F.,
    2. Bradley A.,
    3. Olson E. N.
    (1995) The paired -like homeo box gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev 9, 1237–1249
    OpenUrlAbstract/FREE Full Text
    1. Masuya H.,
    2. Sagai T.,
    3. Wakana S.,
    4. Moriwaki K.,
    5. Shiroishi T.
    (1995) A duplicated zone of polarizing activity in polydactylous mouse mutants. Genes Dev 9, 1645–1653
    OpenUrlAbstract/FREE Full Text
    1. Motzny C.K.,
    2. Holmgren R.
    (1995) The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways. Mech. Dev 52, 137–150
    OpenUrlCrossRefPubMedWeb of Science
    1. Nagy A.,
    2. Rossant J.,
    3. Nagy R.,
    4. Abramow-Newerly W.,
    5. Roder J.
    (1994) Derivation of completely cell culture-derived mice form early-passage. Proc. Natl. Acad. Sci. USA 90, 8424–8428
    OpenUrlAbstract/FREE Full Text
    1. Neubuser A.,
    2. Koseki H.,
    3. Balling R.
    (1995) Characterization anddevelopmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev. Biol 170, 701–716
    OpenUrlCrossRefPubMedWeb of Science
    1. Niswander L.,
    2. Jeffrey S.,
    3. Martin G. R.,
    4. Tickle C.
    (1994) A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 371, 609–612
    OpenUrlCrossRefPubMed
    1. Orenic T. V.,
    2. Slusarski D. C.,
    3. Kroll K. L.,
    4. Holmgren R. A.
    (1990) Cloning and characterization of the segment polarity gene cubitus interruptus Dominant of Drosophila. Genes Dev 4, 1053–1067
    OpenUrlAbstract/FREE Full Text
    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. Riddle R. D.,
    2. Johnson R. L.,
    3. Laufer E.,
    4. Tabin C.
    (1993) Sonic hedgehog mediates the polarizing activity of ZPA. Cell 75, 1401–1416
    OpenUrlCrossRefPubMedWeb of Science
    1. Roberts D. J.,
    2. Johnson R. L.,
    3. Burke A. C.,
    4. Nelson C. E.,
    5. Morgan B. A.,
    6. Tabin C.
    (1995) Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development 121, 3163–3174
    OpenUrlAbstract
    1. Satokata I.,
    2. Maas R.
    (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet 6, 348–355
    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. Theiler K.
    (1988) Vertebral malformations. Adv. Anat. Embryol. Cell Biol 112, 1–99
    OpenUrlPubMed
    1. Tybulewicz V. L. J.,
    2. Crawford C. E.,
    3. KJackson P. K.,
    4. Bronson R. T.,
    5. Mulligan R. C.
    (1991) Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163
    OpenUrlCrossRefPubMedWeb of Science
    1. Vaahtokari A.,
    2. Aberg T.,
    3. Jernvall J.,
    4. Keranen S.,
    5. Thesleff I.
    (1996) The enamel knot as a signaling center in the developing mouse tooth. Mech. Dev 54, 39–43
    OpenUrlCrossRefPubMedWeb of Science
    1. Verbout A. J.
    (1985) The development of the vertebral column. Adv. Anat. Embryol. Cell Biol 90, 1–122
    OpenUrlPubMedWeb of Science
    1. Vortkamp A.,
    2. Gessler M.,
    3. and Grzeschik K.-H.
    (1991) GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540
    OpenUrlCrossRefPubMedWeb of Science
    1. Vortkamp A.,
    2. Franz T.,
    3. Gessler M.,
    4. Grzeschik K.-H.
    (1992) Deletion of GLI3 supports the homology of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutant extra toes (Xt). Mammalian Genome 3, 461–463
    OpenUrlCrossRefPubMedWeb of Science
    1. Vortkamp A.,
    2. Lee K.,
    3. Lanske B.,
    4. Serge G. V.,
    5. Kronenberg H. M.,
    6. Tabin C. J.
    (1996) Regulation of rate of cartilage differentiation by Indian Hedgehog and PTH-related protein. Science 273, 613–622
    OpenUrlAbstract
    1. Wallin J.,
    2. Wilting J.,
    3. Koseki H.,
    4. Fritsch R.,
    5. Christ B.,
    6. Balling R.
    (1994) The role of Pax1 in axial skeleton development. Development 120, 1109–1121
    OpenUrlAbstract
    1. Walterhouse D.,
    2. Ahmed M.,
    3. Slusarski D.,
    4. Kalamaras J.,
    5. Boucher D.,
    6. Holmgren R.,
    7. Iannaccone P.
    (1993) gli, a putative zinc finger transcription factor, is expressed in a segmental pattern during normal mouse development. Dev. Dyn 196, 91–102
    OpenUrlPubMedWeb of Science
    1. Zarkower D.,
    2. Hodgkin J.
    (1993) Zinc fingers in sex determination: only one of the two C. elegans Tra-1 proteins binds DNA in vivo. Nucl.Acids Res 21, 3691–3698
    OpenUrlAbstract/FREE Full Text
Back to top

 Download PDF

Email
JOURNAL ARTICLES
Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development
R. Mo, A.M. Freer, D.L. Zinyk, M.A. Crackower, J. Michaud, H.H. Heng, K.W. Chik, X.M. Shi, L.C. Tsui, S.H. Cheng, A.L. Joyner, C. Hui
Development 1997 124: 113-123;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Advertisement

The people behind the papers – George Britton and Aryeh Warmflash

George and Aryeh

First author George Britton and his supervisor Aryeh Warmflash discuss their new Development paper in which they apply advanced in vitro culturing techniques to investigate embryonic ectoderm patterning.

Travelling Fellowship – New imaging approach unveils a bigger picture

Highlights from Travelling Fellowship trips

Find out how Pamela Imperadore’s Travelling Fellowship grant from The Company of Biologists took her to Germany, where she used new imaging techniques to investigate the cellular machinery underlying octopus arm regeneration. Don’t miss the next application deadline for 2020 travel, coming up on 29 November. Where will your research take you?

Protein function can be controlled by light using optogenetic techniques. In their new Primer, Stefano De Renzis and his colleagues in Heidelberg provide an overview of the most commonly used optogenetic tools and their application in developmental biology.

preLights – Self-organised symmetry breaking in zebrafish reveals feedback from morphogenesis to pattern formation

Sundar Naganathan

preLighter Sundar Naganathan explains his selected preprint by Vikas Trivedi, Benjamin Steventon and their co-workers on pescoids, a new in vitro model system to study early zebrafish embryogenesis.

Spotlight – Can laboratory model systems instruct human limb regeneration?

An extract from a schematic demonstrating the possible pipeline for how discovery in lab model systems can influence applications for regenerative therapies.

One of the most challenging objectives of tissue regeneration research is regrowth of a lost or amputated limb. Here, Ben Cox, Maximina Yun and Kenneth Poss outline the research avenues yet to be explored to move closer to this capstone achievement.

Articles of interest in our sister journals

Tox4 modulates cell fate reprogramming

Lotte Vanheer, Juan Song, Natalie De Geest, Adrian Janiszewski, Irene Talon, Caterina Provenzano, Taeho Oh, Joel Chappell, Vincent Pasque
Journal of Cell Science

Drosophila melanogaster: a simple system for understanding complexity

Stephanie E. Mohr, Norbert Perrimon
Disease Models & Mechanisms