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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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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Positional cloning and characterization of anti-DND1 antibody. (PDF 1531 kb)
Targeted deletion of the Wdr55 gene. (PDF 57 kb)
Expression of Dnd1 in mouse embryo. (JPG 991 kb)
Comparison of DND1 protein sequence to the apobec-1 complementation factor and list of primers that amplify microsatellites from BACs. (PDF 78 kb)
Figure legends for Supplementary Figs 1-3. (RTF 11 kb)
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