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Essential role of Plzf in maintenance of spermatogonial stem cells

Nature Genetics volume 36, pages 653–659 (2004)Cite this article

Abstract

Little is known of the molecular mechanisms whereby spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm1,2. Here we show that Zfp145, encoding the transcriptional repressor Plzf, has a crucial role in spermatogenesis. Zfp145 expression was restricted to gonocytes and undifferentiated spermatogonia and was absent in tubules of W/Wv mutants that lack these cells. Mice lacking Zfp145 underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice before testis degeneration showed alterations in the expression profile of genes associated with spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.

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Figure 1: Expression of Zfp145 in the developing testis.
Figure 2: Mice with a targeted disruption of Zfp145 show testis atrophy.
Figure 3: Proliferation and apoptosis in the developing testis of Zfp145+/+ and Zfp145−/− mice.
Figure 4: Zfp145−/− spermatogonia are unable to repopulate germ cell–depleted recipient testis.
Figure 5: Microarray analysis of gene expression in purified spermatogonia from Zfp145+/+ and Zfp145−/− mice.

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Acknowledgements

We thank A. Viale for advice and discussion regarding microarray analysis; the Molecular Cytology, Flow-Cytometry, Transgenic and Genomic Core facilities, particularly C. Farrell and R. Lester, for technical assistance; E. Pikarsky and X. Wang for providing material; and the members of the laboratory of M.A.D. -B. and P.E. Cohen for discussion. This work is supported by National Center for Research Resources grant, grants from the US National Institutes of Health (to K.E.O. and M.S. and to D.J.W.) and a grant from the National Cancer Institute (to P.P.P.).

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Author notes

  1. José A Costoya

    Present address: Departamento de Fisioloxía, Facultade de Medicina, Universidade de Santiago de Compostela, Rúa San Francisco s/n, 15782, Santiago de Compostela, Spain

  2. José A Costoya and Robin M Hobbs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology Sloan-Kettering Institute, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    José A Costoya, Robin M Hobbs, Maria Barna & Pier Paolo Pandolfi

  2. Institute for Cancer Genetics, Columbia University, 1150 St. Nicholas Ave., New York, 10032, New York, USA

    Giorgio Cattoretti

  3. Developmental Biology Program, Molecular Cytology Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Katia Manova

  4. Departments of Obstetrics, Gynecology & Reproductive Sciences and Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh Development Center of Magee-Womens Research Institute, Pittsburgh, 15213, Pennsylvania, USA

    Meena Sukhwani & Kyle E Orwig

  5. Department of Genetics and Development, Columbia University Medical Center, New York, 10032, New York, USA

    Debra J Wolgemuth

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Correspondence to Pier Paolo Pandolfi.

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Costoya, J., Hobbs, R., Barna, M. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36, 653–659 (2004). https://doi.org/10.1038/ng1367

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