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. 1996 Mar;142(3):965–972. doi: 10.1093/genetics/142.3.965

Evolution of the Hedgehog Gene Family

S Kumar 1, K A Balczarek 1, Z C Lai 1
PMCID: PMC1207033  PMID: 8849902

Abstract

Effective intercellular communication is an important feature in the development of multicellular organisms. Secreted hedgehog (hh) protein is essential for both long- and short-range cellular signaling required for body pattern formation in animals. In a molecular evolutionary study, we find that the vertebrate homologs of the Drosophila hh gene arose by two gene duplications: the first gave rise to Desert hh, whereas the second produced the Indian and Sonic hh genes. Both duplications occurred before the emergence of vertebrates and probably before the evolution of chordates. The amino-terminal fragment of the hh precursor, crucial in long- and short-range intercellular communication, evolves two to four times slower than the carboxyl-terminal fragment in both Drosophila hh and its vertebrate homologues, suggesting conservation of mechanism of hh action in animals. A majority of amino acid substitutions in the amino- and carboxyl-terminal fragments are conservative, but the carboxyl-terminal domain has undergone extensive insertion-deletion events while maintaining its autocleavage protease activity. Our results point to similarity of evolutionary constraints among sites of Drosophila and vertebrate hh homologs and suggest some future directions for understanding the role of hh genes in the evolution of developmental complexity in animals.

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Selected References

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  1. Benton M. J. Phylogeny of the major tetrapod groups: morphological data and divergence dates. J Mol Evol. 1990 May;30(5):409–424. doi: 10.1007/BF02101113. [DOI] [PubMed] [Google Scholar]
  2. Bisbee C. A., Baker M. A., Wilson A. C., Haji-Azimi I., Fischberg M. Albumin phylogeny for clawed frogs (Xenopus). Science. 1977 Feb 25;195(4280):785–787. doi: 10.1126/science.65013. [DOI] [PubMed] [Google Scholar]
  3. Bumcrot D. A., Takada R., McMahon A. P. Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol. 1995 Apr;15(4):2294–2303. doi: 10.1128/mcb.15.4.2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang D. T., López A., von Kessler D. P., Chiang C., Simandl B. K., Zhao R., Seldin M. F., Fallon J. F., Beachy P. A. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development. 1994 Nov;120(11):3339–3353. doi: 10.1242/dev.120.11.3339. [DOI] [PubMed] [Google Scholar]
  5. Echelard Y., Epstein D. J., St-Jacques B., Shen L., Mohler J., McMahon J. A., McMahon A. P. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993 Dec 31;75(7):1417–1430. doi: 10.1016/0092-8674(93)90627-3. [DOI] [PubMed] [Google Scholar]
  6. Fietz M. J., Concordet J. P., Barbosa R., Johnson R., Krauss S., McMahon A. P., Tabin C., Ingham P. W. The hedgehog gene family in Drosophila and vertebrate development. Dev Suppl. 1994:43–51. [PubMed] [Google Scholar]
  7. Francis P. H., Richardson M. K., Brickell P. M., Tickle C. Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limb. Development. 1994 Jan;120(1):209–218. doi: 10.1242/dev.120.1.209. [DOI] [PubMed] [Google Scholar]
  8. Heberlein U., Moses K. Mechanisms of Drosophila retinal morphogenesis: the virtues of being progressive. Cell. 1995 Jun 30;81(7):987–990. doi: 10.1016/s0092-8674(05)80003-0. [DOI] [PubMed] [Google Scholar]
  9. Ingham P. W. Pattern formation. Hedgehog points the way. Curr Biol. 1994 Apr 1;4(4):347–350. doi: 10.1016/s0960-9822(00)00076-2. [DOI] [PubMed] [Google Scholar]
  10. Johnson R. L., Tabin C. The long and short of hedgehog signaling. Cell. 1995 May 5;81(3):313–316. doi: 10.1016/0092-8674(95)90381-x. [DOI] [PubMed] [Google Scholar]
  11. Krauss S., Concordet J. P., Ingham P. W. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell. 1993 Dec 31;75(7):1431–1444. doi: 10.1016/0092-8674(93)90628-4. [DOI] [PubMed] [Google Scholar]
  12. Lai C. J., Ekker S. C., Beachy P. A., Moon R. T. Patterning of the neural ectoderm of Xenopus laevis by the amino-terminal product of hedgehog autoproteolytic cleavage. Development. 1995 Aug;121(8):2349–2360. doi: 10.1242/dev.121.8.2349. [DOI] [PubMed] [Google Scholar]
  13. Lee J. J., von Kessler D. P., Parks S., Beachy P. A. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell. 1992 Oct 2;71(1):33–50. doi: 10.1016/0092-8674(92)90264-d. [DOI] [PubMed] [Google Scholar]
  14. Ma C., Zhou Y., Beachy P. A., Moses K. The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell. 1993 Dec 3;75(5):927–938. doi: 10.1016/0092-8674(93)90536-y. [DOI] [PubMed] [Google Scholar]
  15. Marigo V., Roberts D. J., Lee S. M., Tsukurov O., Levi T., Gastier J. M., Epstein D. J., Gilbert D. J., Copeland N. G., Seidman C. E. Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. Genomics. 1995 Jul 1;28(1):44–51. doi: 10.1006/geno.1995.1104. [DOI] [PubMed] [Google Scholar]
  16. Martí E., Bumcrot D. A., Takada R., McMahon A. P. Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature. 1995 May 25;375(6529):322–325. doi: 10.1038/375322a0. [DOI] [PubMed] [Google Scholar]
  17. Mohler J., Vani K. Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila. Development. 1992 Aug;115(4):957–971. doi: 10.1242/dev.115.4.957. [DOI] [PubMed] [Google Scholar]
  18. Newfeld S. J., Gelbart W. M. Identification of two Drosophila TGF-beta family members in the grasshopper Schistocerca americana. J Mol Evol. 1995 Aug;41(2):155–160. doi: 10.1007/BF00170667. [DOI] [PubMed] [Google Scholar]
  19. Parr B. A., McMahon A. P. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature. 1995 Mar 23;374(6520):350–353. doi: 10.1038/374350a0. [DOI] [PubMed] [Google Scholar]
  20. Perrimon N. Hedgehog and beyond. Cell. 1995 Feb 24;80(4):517–520. doi: 10.1016/0092-8674(95)90503-0. [DOI] [PubMed] [Google Scholar]
  21. Porter J. A., von Kessler D. P., Ekker S. C., Young K. E., Lee J. J., Moses K., Beachy P. A. The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature. 1995 Mar 23;374(6520):363–366. doi: 10.1038/374363a0. [DOI] [PubMed] [Google Scholar]
  22. Riddle R. D., Johnson R. L., Laufer E., Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell. 1993 Dec 31;75(7):1401–1416. doi: 10.1016/0092-8674(93)90626-2. [DOI] [PubMed] [Google Scholar]
  23. Roelink H., Augsburger A., Heemskerk J., Korzh V., Norlin S., Ruiz i Altaba A., Tanabe Y., Placzek M., Edlund T., Jessell T. M. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell. 1994 Feb 25;76(4):761–775. doi: 10.1016/0092-8674(94)90514-2. [DOI] [PubMed] [Google Scholar]
  24. Roelink H., Porter J. A., Chiang C., Tanabe Y., Chang D. T., Beachy P. A., Jessell T. M. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell. 1995 May 5;81(3):445–455. doi: 10.1016/0092-8674(95)90397-6. [DOI] [PubMed] [Google Scholar]
  25. Ruiz i Altaba A., Jessell T. M., Roelink H. Restrictions to floor plate induction by hedgehog and winged-helix genes in the neural tube of frog embryos. Mol Cell Neurosci. 1995 Apr;6(2):106–121. doi: 10.1006/mcne.1995.1011. [DOI] [PubMed] [Google Scholar]
  26. Saitou N., Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. doi: 10.1093/oxfordjournals.molbev.a040454. [DOI] [PubMed] [Google Scholar]
  27. Sidow A., Thomas W. K. A molecular evolutionary framework for eukaryotic model organisms. Curr Biol. 1994 Jul 1;4(7):596–603. doi: 10.1016/s0960-9822(00)00131-7. [DOI] [PubMed] [Google Scholar]
  28. Sitnikova T., Rzhetsky A., Nei M. Interior-branch and bootstrap tests of phylogenetic trees. Mol Biol Evol. 1995 Mar;12(2):319–333. doi: 10.1093/oxfordjournals.molbev.a040205. [DOI] [PubMed] [Google Scholar]
  29. Smith J. C. Hedgehog, the floor plate, and the zone of polarizing activity. Cell. 1994 Jan 28;76(2):193–196. doi: 10.1016/0092-8674(94)90325-5. [DOI] [PubMed] [Google Scholar]
  30. Stolow M. A., Shi Y. B. Xenopus sonic hedgehog as a potential morphogen during embryogenesis and thyroid hormone-dependent metamorphosis. Nucleic Acids Res. 1995 Jul 11;23(13):2555–2562. doi: 10.1093/nar/23.13.2555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tabata T., Kornberg T. B. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell. 1994 Jan 14;76(1):89–102. doi: 10.1016/0092-8674(94)90175-9. [DOI] [PubMed] [Google Scholar]
  32. Tashiro S., Michiue T., Higashijima S., Zenno S., Ishimaru S., Takahashi F., Orihara M., Kojima T., Saigo K. Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication. Gene. 1993 Feb 28;124(2):183–189. doi: 10.1016/0378-1119(93)90392-g. [DOI] [PubMed] [Google Scholar]
  33. Winnepenninckx B., Backeljau T., Mackey L. Y., Brooks J. M., De Wachter R., Kumar S., Garey J. R. 18S rRNA data indicate that Aschelminthes are polyphyletic in origin and consist of at least three distinct clades. Mol Biol Evol. 1995 Nov;12(6):1132–1137. doi: 10.1093/oxfordjournals.molbev.a040287. [DOI] [PubMed] [Google Scholar]
  34. Yang Y., Niswander L. Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Cell. 1995 Mar 24;80(6):939–947. doi: 10.1016/0092-8674(95)90297-x. [DOI] [PubMed] [Google Scholar]
  35. Yang Z. Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods. J Mol Evol. 1994 Sep;39(3):306–314. doi: 10.1007/BF00160154. [DOI] [PubMed] [Google Scholar]
  36. Yang Z., Wang T. Mixed model analysis of DNA sequence evolution. Biometrics. 1995 Jun;51(2):552–561. [PubMed] [Google Scholar]

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