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Heterozygosity with respect to Zfp148 causes complete loss of fetal germ cells during mouse embryogenesis

Nature Genetics volume 33, pages 172–176 (2003)Cite this article

Abstract

Zfp148 belongs to a large family of C2H2-type zinc-finger transcription factors. Zfp148 is expressed in fetal germ cells in 13.5-d-old (E13.5) mouse embryos. Germ-line transmission of mutations were not observed in chimeric Zfp148+/− mice, and some of these mice completely lacked spermatogonia. The number of primordial germ cells in Zfp148+/− tetraploid embryos was normal until E11.5, but declined from E11.5 to E13.5 and continued to decline until few germ cells were present at E18.5. This phenotype was not rescued by wild-type Sertoli or stromal cells, and is therefore a cell-autonomous phenotype. These results indicate that two functional alleles of Zfp148 are required for the normal development of fetal germ cells. Recent studies have shown that Zfp148 activates p53, which has an important role in cell-cycle regulation1. Primordial germ cells stop proliferating at approximately E13.5, which correlates with induction of phosphorylation of p53 and its translocation to the nucleus. Phosphorylation of p53 is impaired in Zfp148+/− embryonic stem cells and in fetal germ cells from chimeric Zfp148+/− embryos. Thus, Zfp148 may be required for regulating p53 in the development of germ cells.

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Figure 1: In situ hybridization of male and female gonads of E12.5 embryos and targeted disruption of Zfp148.
Figure 2: Typical appearance of testes in infertile Zfp148+/− chimeric mice.
Figure 3: Reduction in PGCs in gonads of tetraploid Zfp148+/− chimeric embryos.
Figure 4: Complete loss of pro-spermatogonia in E18.5 mutant chimeric embryos.
Figure 5: Phosphorylated p53 and cell-cycle-arrest induction in control ES cells and its impairment in Zfp148+/− ES cells.
Figure 6: Zfp148 and phosphorylated p53 induction in pro-spermatogonia at E13.5 in the male gonad.

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Acknowledgements

We thank E.M. Eddy, G.-Q. Zhao, Y. Matsui, P. Koopman and R. Newbold for helpful discussion; R. Behringer and A. Bradley for use of AB-1 ES cells; T. Castranio for advice on production of tetraploid chimeras; M. Suzuki for technical advice on blastocyst injection; T.C., G. Scott and S. Kishigami for critical reading of the manuscript; S. Ito for helping experiment of chromosomal count of ES cells; and Y. Takeuchi, Y. and K. Mishina and Chata for encouragement. This study was supported by the Fund for Comprehensive Research on Aging and Health.

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Author notes

  1. Akihide Takeuchi

    Present address: Neural Stem Cell Research, Stem Cells Inc., 3155 Porter Drive, Palo Alto, California, 94304, USA

  2. Osamu Miyaishi

    Present address: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

  3. Tadao Hasegawa

    Present address: Department of Microbiology, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan

Authors and Affiliations

  1. Department of Basic Gerontology, National Institute for Longevity Sciences, 36-3 Gengo, Morioka-cho, Obu-city, 474-8522, Aichi, Japan

    Akihide Takeuchi, Osamu Miyaishi, Eiji Kojima, Tadao Hasegawa & Ken-ichi Isobe

  2. Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA

    Yuji Mishina

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Correspondence to Ken-ichi Isobe.

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Takeuchi, A., Mishina, Y., Miyaishi, O. et al. Heterozygosity with respect to Zfp148 causes complete loss of fetal germ cells during mouse embryogenesis. Nat Genet 33, 172–176 (2003). https://doi.org/10.1038/ng1072

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