The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours

Abstract

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds1. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males2,3,4. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells2,3,4,5,6, and after birth differentiate into various cells and tissues that compose TGCTs. Here, we report the positional cloning of Ter, revealing a point mutation that introduces a termination codon in the mouse orthologue (Dnd1) of the zebrafish dead end (dnd) gene. PGC deficiency is corrected both with bacterial artificial chromosomes that contain Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal gonads during the critical period when TGCTs originate. DND1 has an RNA recognition motif and is most similar to the apobec complementation factor, a component of the cytidine to uridine RNA-editing complex. These results suggest that Ter may adversely affect essential aspects of RNA biology during PGC development. DND1 is the first protein known to have an RNA recognition motif directly implicated as a heritable cause of spontaneous tumorigenesis. TGCT development in the 129-Ter mouse strain models paediatric TGCT in humans. This work will have important implications for our understanding of the genetic control of TGCT pathogenesis and PGC biology.

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Figure 1: Gonadal phenotypes of Ter/Ter males.
Figure 2: Positional cloning of Ter.
Figure 3: Expression of Dnd1 in normal tissues and TGCTs.
Figure 4: Expression of Dnd1 in embryonic gonads.

References

  1. 1

    Sakurai, T., Iguchi, T., Moriwaki, K. & Noguchi, M. The ter mutation first causes primordial germ cell deficiency in ter/ter mouse embryos at 8 days of gestation. Dev. Growth Differ. 37, 293–302 (1995)

    Article  Google Scholar 

  2. 2

    Noguchi, T. & Noguchi, M. A recessive mutation (ter) causing germ cell deficiency and a high incidence of congenital testicular teratomas in 129/Sv-ter mice. J. Natl. Cancer Inst. 75, 385–392 (1985)

    CAS  PubMed  Google Scholar 

  3. 3

    Stevens, L. C. A new inbred subline of mice (129-terSv) with a high incidence of spontaneous congenital testicular teratomas. J. Natl Cancer Inst. 50, 235–242 (1973)

    CAS  Article  Google Scholar 

  4. 4

    Stevens, L. C. & Mackensen, J. A. Genetic and environmental influences on teratocarcinogenesis in mice. J. Natl Cancer Inst. 27, 443–453 (1961)

    Google Scholar 

  5. 5

    Stevens, L. C. Origin of testicular teratomas from primordial germ cells in mice. J. Natl Cancer Inst. 38, 549–552 (1967)

    CAS  PubMed  Google Scholar 

  6. 6

    Donovan, P. J. & de Miguel, M. P. Turning germ cells into stem cells. Curr. Opin. Genet. Dev. 13, 463–471 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Asada, Y., Varnum, D. S., Frankel, W. N. & Nadeau, J. H. A mutation in the Ter gene causing increased susceptibility to testicular teratomas maps to mouse chromosome 18. Nature Genet. 6, 363–368 (1994)

    CAS  Article  Google Scholar 

  8. 8

    Sakurai, T., Katoh, H., Moriwaki, K., Noguchi, T. & Noguchi, M. The ter primordial germ cell deficiency mutation maps near Grl-1 on mouse chromosome 18. Mamm. Genome 5, 333–336 (1994)

    CAS  Article  Google Scholar 

  9. 9

    Weidinger, G. et al. dead end, a novel vertebrate germ plasm component, is required for zebrafish primordial germ cell migration and survival. Curr. Biol. 13, 1429–1434 (2003)

    CAS  Article  Google Scholar 

  10. 10

    Mello, C. C. & Conte, D. Revealing the world of RNA interference. Nature 431, 338–342 (2004)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Shao, J., Sheng, H., Inoue, H., Morrow, J. D. & DuBois, R. N. Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J. Biol. Chem. 275, 33951–33956 (2000)

    CAS  Article  Google Scholar 

  13. 13

    Mukhopadhyay, D., Houchen, C. W., Kennedy, S., Dieckgraefe, B. K. & Anant, S. Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Mol. Cell 11, 113–126 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Yao, H. H., DiNapoli, L. & Capel, B. Meiotic germ cells antagonize mesonephric cell migration and testis cord formation in mouse gonads. Development 130, 5895–5902 (2003)

    CAS  Article  Google Scholar 

  15. 15

    Menke, D. B., Koubova, J. & Page, D. C. Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. Dev. Biol. 262, 303–312 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Scholer, H. R., Dressler, G. R., Balling, R., Rohdewohld, H. & Gruss, P. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 9, 2185–2195 (1990)

    CAS  Article  Google Scholar 

  17. 17

    Mehta, A., Kinter, M. T., Sherman, N. E. & Driscoll, D. M. Molecular cloning of apobec-1 complementation factor, a novel RNA-binding protein involved in the editing of apolipoprotein B mRNA. Mol. Cell. Biol. 20, 1846–1854 (2000)

    CAS  Article  Google Scholar 

  18. 18

    Ma, Z. et al. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genet. 28, 220–221 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Barbouti, A. et al. A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Cancer Res. 63, 1202–1206 (2003)

    CAS  PubMed  Google Scholar 

  20. 20

    Drabkin, H. A. et al. DEF-3 (g16/NY-LU-12), an RNA binding protein from the 3p21.3 homozygous deletion region in SCLC. Oncogene 18, 2589–2597 (1999)

    CAS  Article  Google Scholar 

  21. 21

    Ross, J., Lemm, I. & Berberet, B. Overexpression of an mRNA-binding protein in human colorectal cancer. Oncogene 20, 6544–6550 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Jinawath, N., Furukawa, Y. & Nakamura, Y. Identification of NOL8, a nucleolar protein containing an RNA recognition motif (RRM), which is overexpressed in diffuse-type gastric cancer. Cancer Sci. 95, 430–435 (2004)

    CAS  Article  Google Scholar 

  23. 23

    Tsuei, D.-J. et al. RBMY, a male germ cell-specific RNA-binding protein, activated in human liver cancers and transforms rodent fibroblasts. Oncogene 23, 5815–5822 (2004)

    CAS  Article  Google Scholar 

  24. 24

    Wedekind, J. E., Dance, G. S. C., Sowden, M. P. & Smith, H. C. Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet. 19, 207–216 (2003)

    CAS  Article  Google Scholar 

  25. 25

    Martinho, R. G., Kunwar, P. S., Casanova, J. & Lehmann, R. A noncoding RNA is required for the repression of RNA polII-dependent transcription in primordial germ cells. Curr. Biol. 14, 159–165 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Moore, F. L. et al. Human pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-like proteins. Proc. Natl Acad. Sci. USA 100, 538–543 (2003)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Crittenden, S. L. et al. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 417, 660–663 (2002)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Burd, C. G. & Dreyfuss, G. Conserved structures and diversity of functions of RNA-binding proteins. Science 265, 615–621 (1994)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Yang, X. W., Model, P. & Heintz, N. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nature Biotechnol. 15, 859–865 (1997)

    CAS  Article  Google Scholar 

  30. 30

    Henrique, D. et al. A digoxigenin labeled RNA probe for Sox9 was detected using an alkaline phosphatase-conjugated anti-digoxigenin antibody. Nature 375, 787–790 (1995)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

We thank H. Scholer for the GOF-1/ΔPE/EGFP construct, A. Kong and W. Cosme-Blanco for technical help, G. Lozano for critical reading of the manuscript, and members of the Nadeau laboratory for suggestions. Services of the Trans-NIH Mouse Initiative were used for sequencing BACs encoding the Ter locus. This project was supported by NCI grants to A.M. and J.H.N. and with funds from the NCI and NIH to L.S.S. D.C. and B.C. are funded by a grant from NIH. Veterinary resources, DNA sequencing and Genetically Engineered Mouse Facility were supported by a Cancer Center Support (Core) Grant. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.

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Correspondence to Joseph H. Nadeau or Angabin Matin.

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Supplementary information

Supplementary Figure 1

Positional cloning and characterization of anti-DND1 antibody. (PDF 1531 kb)

Supplementary Figure 2

Targeted deletion of the Wdr55 gene. (PDF 57 kb)

Supplementary Figure 3

Expression of Dnd1 in mouse embryo. (JPG 991 kb)

Supplementary Figure 4

Comparison of DND1 protein sequence to the apobec-1 complementation factor and list of primers that amplify microsatellites from BACs. (PDF 78 kb)

Supplementary Figure Legends

Figure legends for Supplementary Figs 1-3. (RTF 11 kb)

Supplementary Methods

File for additional Methods. (RTF 12 kb)

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Youngren, K., Coveney, D., Peng, X. et al. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435, 360–364 (2005). https://doi.org/10.1038/nature03595

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