Mammalian Genome

, Volume 15, Issue 1, pp 23–34

Phylogenetic conservation of a limb-specific, cis-acting regulator of Sonic hedgehog (Shh)

  • Tomoko Sagai
  • Hiroshi Masuya
  • Masaru Tamura
  • Kunihiko Shimizu
  • Yukari Yada
  • Shigeharu Wakana
  • Yoichi Gondo
  • Tetsuo Noda
  • Toshihiko Shiroishi
Article

Abstract

Polarized expression of the Sonic hedgehog (Shh) gene in the posterior mesenchyme is essential for pattern formation in the appendages of higher vertebrates, from teleost fins to tetrapod limb buds. We report on a sequence in intron 5 of the Lmbr1 gene, which resides approximately 1 Mb from the Shh coding region in the mouse genome and is highly conserved among teleost fishes and throughout the tetrapod lineage. Positional cloning revealed that two mouse mutations, Hx and M100081, characterized by mirror-image digit duplication and ectopic anterior Shh expression, have base substitutions in this sequence. Absence of the conserved sequence in limbless reptiles and amphibians and a cis-trans test using the Hx and Shh KO alleles suggest that the sequence is a cis-acting regulator that controls the polarized expression of Shh.

References

  1. 1.
    Bejder, L, Hall, BK 2002Limbs in whales and limbless in other vertebrates: mechanisms of evolutionary and developmental transformation and loss.Evol Dev4445458CrossRefPubMedGoogle Scholar
  2. 2.
    Blanc, I, Bach, A, Robert, B 2002Unusual patter of Sonic hedgegog expression in the polydactylous mouse mutant hemimelic extra-toes.Int J Dev Biol46969974PubMedGoogle Scholar
  3. 3.
    Carroll, R 1988Vertebrate Paleontology and Evolution.FreemanNew YorkGoogle Scholar
  4. 4.
    Charite, J, MacFadden, DG, Olson, EN 2000The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development.Development12724612470PubMedGoogle Scholar
  5. 5.
    Clack, JA 2002Gaining Ground: The Origin and Evolution of Tetrapods.Indiana University PressBloomington, IndGoogle Scholar
  6. 6.
    Clark, RM, Marker, PC, Kingsley, DM 2000A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice.Genomics671927CrossRefPubMedGoogle Scholar
  7. 7.
    Coghill, EL, Hugill, A, Parkinson, N, Davison, D, Glenister, P,  et al. 2002A gene-driven approach to the identification of ENU mutants in the mouse.Nat Genet30255256CrossRefPubMedGoogle Scholar
  8. 8.
    Cohn, MJ, Tickle, C 1999Developmental basis of limblessness and axial patterning in snakes.Nature399474479CrossRefPubMedGoogle Scholar
  9. 9.
    Drossopoulou, F, Lewis, KE, Sanz-Ezquerro, JJ, Nikbakht, N, McMahon, AP,  et al. 2000A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signaling anf Bmp signaling.Development12713371348PubMedGoogle Scholar
  10. 10.
    Echelard, Y, Epstein, DJ, ST-Jacques, B, Shen, L, Mohler, J,  et al. 1993Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity.Cell7514171430PubMedGoogle Scholar
  11. 11.
    Endo, T, Yokoyama, H, Tamura, K, Ide, H 1997Shh expression in developing and regenerating limb buds of Xenopus laevis.Dev Dyn209227232CrossRefPubMedGoogle Scholar
  12. 12.
    Heus, HC, Hing, A, van Baren, MJ, Joose, M, Breedveld, GJ,  et al. 1999A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36.Genomics57342351CrossRefPubMedGoogle Scholar
  13. 13.
    Heutink, P, Zguricas, J, Oosterhout, Lv, Breedveld, GJ, Testers, L,  et al. 1994The gene for triphalangeal thumb maps to the subtelomellic region of chromosome 7q.Nat Genet6287292PubMedGoogle Scholar
  14. 14.
    Hui, CC, Joyner, AL 1993A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toes J mutation contains an intragenic deletion of the Gli3 gene.Nat Genet3241245PubMedGoogle Scholar
  15. 15.
    Ianakiev, P, van Baren, MJ, Daly, MJ, Toledo, SP, Cavalcanti, MG,  et al. 2001Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene.Am J Hum Genet683845CrossRefPubMedGoogle Scholar
  16. 16.
    Johnson, RL, Tabin, CJ 1997Molecular models for vertebrate limb development.Cell90979990PubMedGoogle Scholar
  17. 17.
    Knudsen, TB, Kochhar, DM 1981The role of morphogenetic cell death during abnormal limb bud outgrowth in mice heterozygous for the dominant mutation Hemimelic-extra toe (Hmx).J Embryol Exp Morphol65289307PubMedGoogle Scholar
  18. 18.
    Koide, T, Moriwaki, K, Uchida, K, Mita, A, Sagai, T,  et al. 1998A new inbred strain JF1 established from Japanese fancy mouse carrying the classic piebald allele.Mamm Genome91519CrossRefPubMedGoogle Scholar
  19. 19.
    Krauss, S, Concordet, JP, Ingham, PW 1993A functionally conserved homolog of the Drosophila segment polarity gene hedgehog is expressed in tissues with polarizing activity in zebrafish embryos.Cell7514311444PubMedGoogle Scholar
  20. 20.
    Lettice, LA, Horikoshi, T, Heaney, SJ, Baren, MJ, van der Linde, HC,  et al. 2002Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.Proc Natl Acad Sci USA9975437553CrossRefGoogle Scholar
  21. 21.
    Lettice, LA, Heaney, SJ, Purdie, LA, Li, L, De Beer, P,  et al. 2003A long-range Shh enhancer regulates expression in the developing limb and fin is associated with preaxial polydactyly.Hum Mol Genet1217251735CrossRefPubMedGoogle Scholar
  22. 22.
    Litingtung, Y, Dahn, RD, Li, Y, Fallon, JF, Chiang, C 2002Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity.Nature418979983CrossRefPubMedGoogle Scholar
  23. 23.
    Martin, GR, Richman, M, Reinsert, S, Nadeau, JH, Joyner, A 1990Mapping of the two mouse engrailed-like genes: close linkage of En-1 to dominant hemimelia (Dh) on chromosome 1 and of En-2 to hemimelic extra-toes (Hx) on chromosome 5.Genomics6302308PubMedGoogle Scholar
  24. 24.
    Masuya, H, Sagai, T, Wakana, S, Moriwaki, K, Shiroishi, T 1995A duplicated zone of polarizing activity in polydactylous mouse mutants.Genes Dev916451653PubMedGoogle Scholar
  25. 25.
    Masuya, H, Sagai, T, Moriwaki, K, Shiroishi, T 1997Multigenic crontrol of the localization of the zone of polarizing activity in limb morphogenesis in the mouse.Dev Biol1824251CrossRefPubMedGoogle Scholar
  26. 26.
    Niswander, L, Martin, GR 1992Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse.Development114755768PubMedGoogle Scholar
  27. 27.
    Qu, S, Niswander, KD, Ji, Q, ven der Meer, R, Keeney, D, Magnuson, MA, Wisdom, R 1997Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.Development12439994008PubMedGoogle Scholar
  28. 28.
    Riddle, RD, Johnson, RL, Laufer, E, Tabin, C 1993Sonic hedgehog mediates the polarizing activity of ZPA.Cell7514011416PubMedGoogle Scholar
  29. 29.
    Sasaki, H 1995cDNA selection by in-solution hybridization.Jikken Igaku138793Google Scholar
  30. 30.
    Saunders, JW, Gasseling, MT 1968

    Ectodermal-mesenchymal interactions in the origin of limb symmetry.

    Fleischmajor, RBillingham, RE eds. Epithelial-Mesenxhymal Interactions.Williams and WilkinsBaltimore7897
    Google Scholar
  31. 31.
    Sharpe, J, Lettice, L, Hecksher-Sorensen, J, Fox, M, Hill, R, Krumlauf, R 1999Identification of sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch.Curr Biol997100CrossRefPubMedGoogle Scholar
  32. 32.
    Shimamura, M, Yasue, H, Ohshima, K, Abe, H, Kato, H,  et al. 1997Molecular evidence from retroposons that whales form a clade within even-toed ungulates.Nature388666670CrossRefPubMedGoogle Scholar
  33. 33.
    Sivastava, D, Cserjesi, P, Olson, EN 1995A subclass of bHLH proteins required for cardiac morphogenesis.Science27019951999PubMedGoogle Scholar
  34. 34.
    Tabin, CJ 1992Why we have (only) five fingers per hand: hox genes and the evolution of paired limbs.Development116289296PubMedGoogle Scholar
  35. 35.
    Tanaka, M, Munsterberg, A, Anderson, WG, Prescott, AR, Hazon, N,  et al. 2002Fin development in a cartilaginous fish and the origin of vertebrate limbs.Nature416527531PubMedGoogle Scholar
  36. 36.
    te Welsher, P, Fernandez-Teran, M, Ros, MA, Zeller, R 2002aMutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling.Genes Dev16421426Google Scholar
  37. 37.
    te Welscher, P, Zuniga, A, Kuijper, S, Drenth, T, Goedemans, HJ,  et al. 2002bProgression of vertebrate limb development through SHH-mediated counteraction of GLI3.Science298827830Google Scholar
  38. 38.
    Thacher, J 1877Median and paired fins, a contribution to the history of vertebrate limbs.Trans Conn Acad3281310Google Scholar
  39. 39.
    Torok, MA, Gardner, DM, Izpisua-Belmonte, JC, Bryant, SV 1999Sonic hedgehog (shh) expression in developing and regenerating axolotl limbs.J Exp Zool284197206CrossRefPubMedGoogle Scholar
  40. 40.
    Tsukurov, O, Boehmer, A, Flynn, J, Nicolai, JP, Hamel, BC,  et al. 1994A complex bilateral polysyndactyly disease locus maps to chromosome 7q36.Nat Genet6282286PubMedGoogle Scholar
  41. 41.
    Wallin, J, Wilting, J, Koseki, H, Fritsch, R, Christ, B, Balling, R 1994The role of Pax-1 in axial skeleton development.Development12011091121PubMedGoogle Scholar
  42. 42.
    Wang, B, Fallon, JF, Beachy, PA 2000Hedgehog-regulated processing of Gli3 produces an anterior/posterior represser gradient in the developing vertebrate limb.Cell100423434PubMedGoogle Scholar
  43. 43.
    Wilkinson, DG 1992In Situ Hybridization: A Practical Approach.Oxford University PressOxford, UKGoogle Scholar
  44. 44.
    Yang, Y, Drossopoulou, G, Chuang, PT, Duprez, D, Marti, E,  et al. 1997Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb.Development12443934404PubMedGoogle Scholar
  45. 45.
    Zhu, M, Yu, X 2002A primitive fish close to the common ancestor of tetrapods and lungfish.Nature418767770CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 2004

Authors and Affiliations

  • Tomoko Sagai
    • 1
  • Hiroshi Masuya
    • 2
  • Masaru Tamura
    • 1
  • Kunihiko Shimizu
    • 3
  • Yukari Yada
    • 1
  • Shigeharu Wakana
    • 2
  • Yoichi Gondo
    • 4
  • Tetsuo Noda
    • 2
  • Toshihiko Shiroishi
    • 1
    • 2
  1. 1.Mammalian Genetics LaboratoryNational Institute of Genetics, Yata-1111, Mishima, Shizuoka-ken 411-8540Japan
  2. 2.Mouse Functional Genomics Research GroupRiken Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa 244-0804Japan
  3. 3.Department of PedodonticsNihon University Graduate School of Dentistry at Matudo, 2-870-1 Sakaecho-Nishi, Matudo, Chiba, 271Japan
  4. 4.Population and Quantitative Genomics TeamBioinformatics Group, Riken Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa 244-0804Japan

Personalised recommendations