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From Oligodactyly to Polydactyly

Role of Shh and Gli3 in Limb Morphogenesis

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Hedgehog-Gli Signaling in Human Disease

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

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Abstract

Secreted molecules encoded by the Hedgehog (Hh) gene family have emerged as key signals in regulating the growth and patterning of invertebrate and vertebrate embryos. One of the most prominent features among Hh members is thought to reside in their ability to impose distinct cell fates in a concentration-dependent manner. This ability is highlighted by the critical and indispensable role of Sonic hedgehog (Shh) signaling in specifying the anterior-posterior polarity of the embryonic limb. Alteration of Shh expression and signaling activity can lead to profound developmental abnormalities in digit numbers and identity in mice and humans. In this chapter, we discuss the Shh regulatory mechanism that establishes the anterior-posterior polarity of the limb and how misregulation of this mechanism can lead to severe limb malformations in humans.

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References

  1. Tickle C. Patterning systems—from one end of the limb to the other. Dev Cell 2003; 4(4):449–458.

    Article  PubMed  CAS  Google Scholar 

  2. Martin GR. The roles of FGFs in the early development of vertebrate limbs. Genes Dev 1998; 12:1571–1586.

    PubMed  CAS  Google Scholar 

  3. Saunders JW, Gasseling M. Ectodermal-mesenchymal interaction in the origin of limb symmetry. In: Fleischmayer R, Billingham RE, eds. Epithelial-mesenchymal interaction. Baltimore: Williams and Wilkins, 1968:78097.

    Google Scholar 

  4. Tickle C. The number of polarizing region cells required to specify additional digits in the developing chick wing. Nature 1981; 289:295–298.

    Article  PubMed  CAS  Google Scholar 

  5. Chang DT, Lopez A, von Kessler DP et al. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 1994; 120:3339–3353.

    PubMed  CAS  Google Scholar 

  6. Lopez-Martinez A, Chang DT, Chiang C et al. Limb-patterning activity and restricted posterior localization of the amino-terminal product of Sonic hedgehog cleavage. Current Biology 1995; 5:791–796.

    Article  PubMed  CAS  Google Scholar 

  7. Riddle RD, Johnson RL, Laufer E et al. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993; 75:1401–1416.

    Article  PubMed  CAS  Google Scholar 

  8. Chiang C, Litingtung Y, Harris MP et al. Manifestation of the limb prepattern: Limb development in the absence of sonic hedgehog function. Dev Biol 2001; 236(2):421–435.

    Article  PubMed  CAS  Google Scholar 

  9. Kraus P, Fraidenraich D, Loomis CA. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech Dev 2001; 100(1):45–58.

    Article  PubMed  CAS  Google Scholar 

  10. Lewis PM, Dunn MP, McMahon JA et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001; 105(5):599–612.

    Article  PubMed  CAS  Google Scholar 

  11. Qu S, Tucker SC, Ehrlich JS et al. Mutations in mouse Aristaless-like4 cause Strong’s luxoid polydactyly. Development 1998; 125(14):2711–2721.

    PubMed  CAS  Google Scholar 

  12. Lettice LA, Heaney SJ, Purdie LA et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 2003; 12(14):1725–1735.

    Article  PubMed  CAS  Google Scholar 

  13. Sagai T, Masuya H, Tamura M et al. Phylogenetic conservation of a limb-specific, cis-acting regulator of Sonic hedgehog (Shh). Mamm Genome 2004; 15(1):23–34.

    Article  PubMed  CAS  Google Scholar 

  14. Qu S, Tucker SC, Ehrlich JS et al. Mutaions in mouse aristaless-like4 cause strong’s luxoid polydactyly. Development 1998; 125:2711–2721.

    PubMed  CAS  Google Scholar 

  15. Qu S, Niswender KD, Ji Q et al. Polydactyly and ectopic ZPA formation in Alx-4 mutant mice. Development 1997; 124(20):3999–4008.

    PubMed  CAS  Google Scholar 

  16. te Welscher P, Zuniga A, Kuijper S et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science 2002; 298(5594):827–830.

    Article  Google Scholar 

  17. Lettice LA, Horikoshi T, Heaney SJ et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci USA 2002; 99(11):7548–7553.

    Article  PubMed  CAS  Google Scholar 

  18. Clark RM, Marker PC, Kingsley DM. A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice. Genomics 2000; 67(1):19–27.

    Article  PubMed  CAS  Google Scholar 

  19. Hill RE, Heaney SJ, Lettice LA. Sonic hedgehog: Restricted expression and limb dysmorphologies. J Anat 2003; 202(1):13–20.

    Article  PubMed  CAS  Google Scholar 

  20. Maas SA, Fallon JF. Isolation of the chicken Lmbr1 coding sequence and characterization of its role during chick limb development. Dev Dyn 2004; 229(3):520–528.

    Article  PubMed  CAS  Google Scholar 

  21. Castilla EE, Lugarinho da Fonseca R, da Graca Dutra M et al. Epidemiological analysis of rare polydactylies. Am J Med Genet 1996; 65(4):295–303.

    Article  PubMed  CAS  Google Scholar 

  22. Temtamy SA, McKusick VA. The genetics of hand malformations. Birth Defects Orig Artic Ser 1978; 14(3):(i–xviii), 1–619.

    PubMed  CAS  Google Scholar 

  23. Heutink P, Zguricas J, van Oosterhout L et al. The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nat Genet 1994; 6(3):287–292.

    Article  PubMed  CAS  Google Scholar 

  24. Tsukurov O, Boehmer A, Flynn J et al. A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nat Genet 1994; 6(3):282–286.

    Article  PubMed  CAS  Google Scholar 

  25. Zguricas J, Heus H, Morales-Peralta E et al. Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36. J Med Genet 1999; 36(1):32–40.

    PubMed  CAS  Google Scholar 

  26. Ianakiev P, van Baren MJ, Daly MJ et al. Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am J Hum Genet 2001; 68(1):38–45.

    Article  PubMed  CAS  Google Scholar 

  27. Clark RM, Marker PC, Roessler E et al. Reciprocal mouse and human limb phenotypes caused by gain-and loss-of-function mutations affecting Lmbr1. Genetics 2001; 159(2):715–726.

    PubMed  CAS  Google Scholar 

  28. Ingham PW, McMahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev 2001; 15(23):3059–3087.

    Article  PubMed  CAS  Google Scholar 

  29. Mo R, Freer AM, Zinyk DL et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 1997; 124(1):113–123.

    PubMed  CAS  Google Scholar 

  30. Park HL, Bai C, Platt KA et al. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 2000; 127(8):1593–1605.

    PubMed  CAS  Google Scholar 

  31. Johnson DR. Extra-toes: A new mutant gene causing multiple abnormalities in the mouse. J Embyol Exp Morph 1967; 17:543–581.

    CAS  Google Scholar 

  32. Hui CC, Joyner AL. A mouse model of greig cephalopolysyndactyly syndrome: The extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nature Genetics 1993; 3(3):241–246.

    Article  PubMed  CAS  Google Scholar 

  33. Masuya H, Sagai T, Moriwaki K et al. Multigenic control of the localization of the zone of polarizing activity in limb morphogenesis in the mouse. Dev Biol 1997; 182(1):42–51.

    Article  PubMed  CAS  Google Scholar 

  34. Buscher D, Ruther U. Expression profile of Gli family members and Shh in normal and mutant mouse limb development. Developmental Dynamics 1998; 211(1):88–96.

    Article  PubMed  CAS  Google Scholar 

  35. Litingtung Y, Dahn RD, Li Y et al. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 2002; 418(6901):979–983.

    Article  PubMed  CAS  Google Scholar 

  36. Dai P, Akimaru H, Tanaka Y et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 1999; 274(12):8143–8152.

    Article  PubMed  CAS  Google Scholar 

  37. Ruiz i Altaba A. Gli proteins encode context-dependent positive and negative functions: Implications for development and disease. Development 1999; 126(14):3205–3216.

    PubMed  Google Scholar 

  38. Sasaki H, Nishizaki Y, Hui C et al. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: Implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 1999; 126(17):3915–3924.

    PubMed  CAS  Google Scholar 

  39. Shin SH, Kogerman P, Lindstrom E et al. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci USA 1999; 96(6):2880–2884.

    Article  PubMed  CAS  Google Scholar 

  40. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000; 100(4):423–434.

    Article  PubMed  CAS  Google Scholar 

  41. Caruccio NC, Martinez-Lopez A, Harris M et al. Constitutive activation of sonic hedgehog signaling in the chicken mutant talpid(2): Shh-independent outgrowth and polarizing activity [In Process Citation]. Dev Biol 1999; 212(1):137–149.

    Article  PubMed  CAS  Google Scholar 

  42. Wild A, Kalff-Suske M, Vortkamp A et al. Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet 1997; 6(11):1979–1984.

    Article  PubMed  CAS  Google Scholar 

  43. Kang S, Graham Jr JM, Olney AH et al. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 1997; 15(3):266–268.

    Article  PubMed  CAS  Google Scholar 

  44. Radhakrishna U, Wild A, Grzeschik KH et al. Mutation in GLI3 in postaxial polydactyly type A [letter]. Nat Genet 1997; 17(3):269–271.

    Article  PubMed  CAS  Google Scholar 

  45. Biesecker LG. Strike three for GLI3. Nature Genetics 1997; 17(3):259–260.

    Article  PubMed  CAS  Google Scholar 

  46. Radhakrishna U, Bornholdt D, Scott HS et al. The Phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 1999; 65(3):645–655.

    Article  PubMed  CAS  Google Scholar 

  47. Kalff-Suske M, Wild A, Topp J et al. Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet 1999; 8(9):1769–1777.

    Article  PubMed  CAS  Google Scholar 

  48. Debeer P, Peeters H, Driess S et al. Variable phenotype in Greig cephalopolysyndactyly syndrome: Clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet 2003; 120A(1):49–58.

    Article  Google Scholar 

  49. Masuya H, Sagai T, Wakana S et al. A duplicated zone of polarizing activity in polydactylous mouse mutants. Genes Dev 1995; 9:1645–1653.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Ave. South, Nashville, Tennessee, 37232, USA

    Chin Chiang

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  1. Chin Chiang
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Chiang, C. (2006). From Oligodactyly to Polydactyly. In: Hedgehog-Gli Signaling in Human Disease. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-33777-6_11

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