Mammalian Genome

, Volume 8, Issue 12, pp 879–883

Ftl, a novel gene related to ubiquitin-conjugating enzymes, is deleted in the Fused toes mouse mutation

  • Ralf Lesche
  • Astrid Peetz
  • Frank van der Hoeven
  • Ulrich Rüther
Original Contribution


The dominant mouse mutation Fused toes is characterized by partial syndactyly of the limbs and thymic hyperplasia. Both morphological abnormalities were shown to be related to impaired regulation of programmed cell death. Ft/Ft embryos die in midgestation showing severe malformations of fore- and mid-brain as well as randomized situs. In Ft mice a large chromosomal deletion (about 300 kb) occurred after insertional mutagenesis. In this report we describe the identification of the first gene that has been mutated by Fused toes. The expression of the novel gene Ftl is reduced in Ft/+ mice and completely absent in Ft/Ft embryos. Analysis of the Ftl cDNA revealed an open reading frame that could code for a 32-kDa protein with similarities to ubiquitin-conjugating enzymes. Ftl transcripts with alternative 5′ UTR sequences as well as differential usage of polyadenylation sites were found. Interestingly, the 3’ parts of the longest Ftl transcripts are identical to the reverse complement of the 3′-most sequences of the Rb-related pl30 gene. Both genes are transcribed in opposite directions and overlap in their 3′ UTRs. Despite the close linkage, pl30 expression appeared not to be affected by the Ft mutation. In wild type mice, Ftl expression levels were found to be high in brain, kidney, and testes and detectable in all other adult organs and throughout embryonic development. Finally, we show that Ftl is conserved among mammals and identify the human homolog.


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  1. Bedell MA, Jenkins NA, Copeland NG (1997a) Mouse models of human disease. Part I: Techniques and resources for genetic analysis in mice. Genes Dev 11, 1–10PubMedCrossRefGoogle Scholar
  2. Bedell MA, Largaespada DA, Jenkins NA, Copeland NG (1997b) Mouse models of human disease. Part II: Recent progress and future directions. Genes Dev 11, 11–43PubMedCrossRefGoogle Scholar
  3. Chen G, Guy, CT, Chen H-W, Hu N, Lee EY-HP, Lee W-H (1996) Molecular cloning and developmental expression of mouse p130, a member of the retinoblastoma gene-Family. J Biol Chem 271, 9567–9572PubMedCrossRefGoogle Scholar
  4. Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79, 13–21PubMedCrossRefGoogle Scholar
  5. Curtis D, Lehmann R, Zamore PD (1995) Translational regulation in development. Cell 81, 171–178PubMedCrossRefGoogle Scholar
  6. Frohman MA, Dash MK, Martin GR (1988) Rapid production of full length cDNAs from rare transcripts: amplification using one single gene specific oligonucleotide primer. Proc Natl Acad Sci USA 85, 8998–9002PubMedCrossRefGoogle Scholar
  7. Gavis ER, Lehmann R (1992) Localization of nanos RNA controls embryonic polarity. Cell 71, 301–313PubMedCrossRefGoogle Scholar
  8. Heymer J, Kuehn MR, Rüther U (1997) The expression pattern of nodal and lefty in the mouse mutant Fused toes suggests a function in the establishment of handedness. Mech Dev, in pressGoogle Scholar
  9. Jackson-Grusby L, Kuo A, Leder P (1992) A variant limb deformity transcript expressed in the embryonic mouse limb defines a novel formin. Genes Dev 6, 29–37PubMedCrossRefGoogle Scholar
  10. Jentsch S (1992) The ubiquitin-conjugation system. Annu Rev Genet 26, 179–207PubMedCrossRefGoogle Scholar
  11. Khan AS, Wilcox AS, Polymeropoulos MH, Hopkins JA, Stevens TJ, Robinson M, Orpana AK, Sikela JM (1992) Single pass sequencing and physical mapping of human cDNAs. Nature Genet 2, 180–185PubMedCrossRefGoogle Scholar
  12. Kozak M (1989) Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol Cell Biol 9, 5134–5142PubMedGoogle Scholar
  13. LeCouter JE, Whyte PFM, Rudnicki MA (1996) Cloning and expression of the Rb-related mouse pl30 mRNA. Oncogene 12, 1433–1440PubMedGoogle Scholar
  14. Li Y, Graham C, Lacy S, Duncan AMV, Whyte P (1993) The adenovirus ElA-associated 130 kd Protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev 7, 2366–2377PubMedCrossRefGoogle Scholar
  15. Lyon MF, Searle AG (1989) Genetic variants and strains of the laboratory mouse. (Stuttgart, Germany: Gustav Fischer Verlag)Google Scholar
  16. Nagata S, Golstein P (1995) The Fas death factor. Science 267, 1449–1456PubMedCrossRefGoogle Scholar
  17. Pertile P, Baldi A, De Luca A, Bagella L, Virgilio L, Pisano MM, Giordano A (1996) Molecular cloning, expression and developmental characterization of the murine retinoblastoma-related gene Rb2/pl30. Cell Growth Differ 6, 1659–1664Google Scholar
  18. Richter JD (1995) Dynamics of poly (A) addition and removal during development. in Translational Control, M. Mathews, J. Hershey, N. Sonnenberg, eds. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press), pp. 00-00Google Scholar
  19. van der Hoeven F, Schimmang T, Volkmann A, Mattei M-G, Kyewski B, Rüther U (1994) Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120, 2601–2607PubMedGoogle Scholar
  20. Whyte P (1995) The retinoblastoma protein and its relatives. Semin Cancer Biol 6, 83–90PubMedCrossRefGoogle Scholar
  21. Woychik RP, Maas RL, Zeller R, Vogt TF, Leder P (1990) Formins: proteins deduced from the alternative transcripts of the limb deformity gene. Nature 346, 850–853PubMedCrossRefGoogle Scholar
  22. Yeung RS, Bell DW, Testa JR, Mayol X, Baldi A, Grana X, Klinga-Levan K, Knudson AG, Giordano A (1993) The retinoblastoma-related gene, RB2, maps to human chromosome 16ql2 and rat chromosome 19. Oncogene 8, 3465–3468PubMedGoogle Scholar
  23. Zakeri Z, Quaglino D, Ahuja HS (1994) Apoptotic death in the mouse limb and its suppression in the Hammertoe mutant. Dev Biol 165, 294–297PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Ralf Lesche
    • 1
  • Astrid Peetz
    • 1
  • Frank van der Hoeven
    • 1
  • Ulrich Rüther
    • 1
  1. 1.Institut für Molekularbiologie, OE 5250Medizinische Hochschule HannoverHannoverGermany
  2. 2.EMBLHeidelbergGermany

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