Calcified Tissue International

, Volume 77, Issue 1, pp 23–29

Tooth Enamel Defects in Mice with a Deletion at the Arhgap6/AmelX Locus

  • S. K. Prakash
  • C. W. Gibson
  • J. T. Wright
  • C. Boyd
  • T. Cormier
  • R. Sierra
  • Y. Li
  • W. R. Abrams
  • M. A. Aragon
  • Z. A. Yuan
  • I. B. van den Veyver
Article

Abstract

The amelogenin proteins regulate enamel mineral formation in the developing tooth. The human AMELX gene, which encodes the amelogenin proteins, is located within an intron of the Arhgap6gene. ARHGAP6 encodes a RhoGAP, which regulates activity of RhoA, a small G protein involved in intracellular signal transduction. Mice were generated in which the entire ARHGAP6 gene was deleted by Cre-mediated recombination, which also removed the nested AmelX gene. Enamel from these mice appeared chalky white, and the molars showed excessive wear. The enamel layer was hypoplastic and nonprismatic, whereas other dental tissues had normal morphology. This phenotype is similar to that reported for AmelX null mice, which have a short deletion that removed the region surrounding the translation initiation site, and resembles some forms of X-linked amelogenesis imperfecta in humans. Analysis of the enamel from the Arhgap6/AmelX-deleted mice verifies that the AmelX gene is nested within the murine Arhgap6 gene and shows that removal of the entire AmelX gene leads to a phenotype similar to the earlier AmelX null mouse results, in which no amelogenin protein was detected. However, an unusual layer of aprismatic enamel covers the enamel surface, which may be related to the 1.1-Mb deletion, which included Arhgap6 in these mice.

Keywords

Amelogenin Arhgap6 amelogenesis imperfecta enamel Cre lox recombination 

References

  1. 1.
    Termine, JD, Belcourt, AB, Christner, PJ, Conn, KM, Nylen, MU 1980Properties of dissociatively extracted fetal tooth matrix proteinsI. Principal molecular species in developing bovine enamel. J Biol Chem25597609768Google Scholar
  2. 2.
    Robinson, C, Brookes, SJ, Shore, RC, Kirkham, J 1998The developing enamel matrix: nature and functionEur J Oral Sci 106 Suppl1282291Google Scholar
  3. 3.
    Lagerstrom, M, Dahl, N, Nakahori, Y, Nakagome, Y, Backman, B, Landegren, U,  et al. 1991A deletion in the amelogenin gene (AMG) causes X-linked amelogenesis imperfecta (AIH1)Genomics10971975CrossRefPubMedGoogle Scholar
  4. 4.
    Hart, PS, Hart, TC, Simmer, JP, Wright, JT 2002A nomenclature for X-linked amelogenesis imperfectaArch Oral Biol47255260CrossRefPubMedGoogle Scholar
  5. 5.
    Diekwisch, T, David, S, Bringas, P,Jr, Santos, V, Slavkin, HC 1993Antisense inhibition of AMEL translation demonstrates supramolecular controls for enamel HAP crystal growth during embryonic mouse molar developmentDevelopment117471482PubMedGoogle Scholar
  6. 6.
    Lyngstadaas, SP, Risnes, S, Sproat, BS, Thrane, PS, Prydz, HP 1995A synthetic, chemically modified ribozyme eliminates amelogenin, the major translation product in developing mouse enamel in vivoEMBO J1452245229PubMedGoogle Scholar
  7. 7.
    Gibson, CW, Yuan, ZA, Hall, B, Longenecker, G, Chen, E, Thyagarajan, T, Sreenath, T, Wright, JT, Decker, S, Piddington, R, Harrison, G, Kulkarni, AB 2001Amelogenin-deficient mice display an amelogenesis imperfecta phenotypeJ Biol Chem2763187131875CrossRefPubMedGoogle Scholar
  8. 8.
    Nakahori Y, Takenaka O, Nakagome Y (1991) A human X-Y homologous region encodes “amelogenin”. Genomics 9:264–269CrossRefPubMedGoogle Scholar
  9. 9.
    Salido, EC, Yen, PH, Koprivnikar, K, Yu, LC, Shapiro, LJ 1992The human enamel protein gene amelogenin is expressed from both the X and Y chromosomesAm J Hum Genet50303316PubMedGoogle Scholar
  10. 10.
    Lau, EC, Mohandas, TK, Shapiro, LJ, Slavkin, HC, Snead, ML 1989Human and mouse amelogenin gene loci are on the sex chromosomesGenomics4162168CrossRefPubMedGoogle Scholar
  11. 11.
    Gibson, CW, Golub, EE, Abrams, WR, Shen, G, Ding, W, Rosenbloom, J 1992Bovine amelogenin message heterogeneity: alternative splicing and Y-chromosomal gene transcriptionBiochemistry3183848388CrossRefPubMedGoogle Scholar
  12. 12.
    Bailey, DMD, Affara, NA, Ferguson-Smith, MA 1992The X-Y homologous gene amelogenin maps to the short arms of both the X and Y chromosomes and is highly conserved in primatesGenomics14203205CrossRefPubMedGoogle Scholar
  13. 13.
    Girandot, M, Sire, J-Y 1998Evolution of the amelogenin gene in toothed and toothless vertebratesEur J Oral Sci106501508PubMedGoogle Scholar
  14. 14.
    Prakash, SK, Paylor, R, Jenna, S, Lamarche-Vane, N, Armstrong, DL, Xu, B, Mancini, MA, Zoghbi, HY 2000Functional analysis of ARHGAP6, a novel GTPase activating protein for RhoAHum Mol Genet9477488CrossRefPubMedGoogle Scholar
  15. 15.
    Schaefer, L, Prakash, S, Zoghbi, HY 1997Cloning and characterization of a novel rho-type GTPase-activating protein gene (ARHGAP6) from the critical region for microphthalmia with linear skin defectsGenomics46268277CrossRefPubMedGoogle Scholar
  16. 16.
    Etienne-Manneville, S, Hall, A 2002Rho GTPases in cell biologyNature420629635CrossRefPubMedGoogle Scholar
  17. 17.
    Ridley, AJ 1997The GTP-binding protein RhoInt J Biochem Cell Biol2912251229CrossRefPubMedGoogle Scholar
  18. 18.
    Aelst, L, D’Souza-Schorey, C 1997Rho GTPases and signaling networksGenes Devel1122952322PubMedGoogle Scholar
  19. 19.
    Veyver, IB, Cormier, TA, Jurecic, V, Baldini, A, Zoghbi, HY 1998Characterization and physical mapping in human and mouse of a novel RING finger gene in Xp22Genomics51251261CrossRefPubMedGoogle Scholar
  20. 20.
    Prakash, SK, Cormier, TA, McCall, AE, Garcia, JJ, Sierra, R, Haupt, B, Zoghbi, HY, Veyver, IB 2002Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndromeHum Molec Genet1132373248CrossRefPubMedGoogle Scholar
  21. 21.
    Zheng, B, Mills, AA, Bradley, A 1999A system for rapid generation of coat color-tagged knockouts and defined chromosomal rearrangements in miceNucleic Acids Res2723542360CrossRefPubMedGoogle Scholar
  22. 22.
    Lakso, M, Pichel, JG, German, JR, Sauer, B, Okamoto, Y, Lee, E, Alt, FW, Westphal, H 1996Efficient in vivo manipulation of mouse genomic sequences at the zygote stageProc Natl Acad Sci USA9358605865CrossRefPubMedGoogle Scholar
  23. 23.
    Hirotsune, S, Fleck, MW, Gambello, MJ, Bix, GJ, Chen, A, Clark, GD, Ledbetter, DH, McBain, CJ, Wynshaw-Boris, A 1998Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethalityNat Genet19333339CrossRefPubMedGoogle Scholar
  24. 24.
    Gibson, CW, Thomson, NH, Abrams, WR, Kirkham, J (2005) Nested genes: biological implications and use of AFM for analysis. Gene 350: 15–23CrossRefPubMedGoogle Scholar
  25. 25.
    Li, W, Mathews, C, Gao, C, DenBesten, PK 1998Identification of two additional exons at the 3′ end of the amelogenin geneArch Oral Biol43497504CrossRefPubMedGoogle Scholar
  26. 26.
    Baba, O, Takahashi, N, Terashima, T, Li, W, DenBesten, PK, Takano, Y 2002Expression of alternatively spliced RNA transcripts of amelogenin gene exons 8 and 9 and its end products in the rat incisorJ Histochem Cytochem5012291236PubMedGoogle Scholar
  27. 27.
    Hall, A 1998Rho GTPases and the actin cytoskeletonScience279509514CrossRefPubMedGoogle Scholar
  28. 28.
    Smith, CE, McKee, MD, Nanci, A 1987Cyclic induction and rapid movement of sequential waves of new smooth-ended ameloblast modulation bands in rat incisors as visualized by polychrome fluorescent labeling and GBHA-staining of maturing enamelAdv Dent Res1162175PubMedGoogle Scholar
  29. 29.
    Nishikawa, S, Josephsen, K 1987Cyclic localization of actin and its relationship to junctional complexes in maturation ameloblasts of the rat incisorAnat Rec2192131CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • S. K. Prakash
    • 1
    • 2
  • C. W. Gibson
    • 3
  • J. T. Wright
    • 4
  • C. Boyd
    • 4
  • T. Cormier
    • 1
  • R. Sierra
    • 5
  • Y. Li
    • 3
  • W. R. Abrams
    • 3
  • M. A. Aragon
    • 3
  • Z. A. Yuan
    • 3
  • I. B. van den Veyver
    • 1
    • 5
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of Internal MedicineBaylor College of MedicineHoustonUSA
  3. 3.Department of Anatomy and Cell Biology Univ. of Pennsylvania School of Dental MedicinePhiladelphiaUSA
  4. 4.Department of Pediatric Dentistry Univ. of North CarolinaChapel HillUSA
  5. 5.Department of Obstetrics and GynecologyBaylor College of MedicineHoustonUSA

Personalised recommendations