The Transition from Stem Cell to Progenitor Spermatogonia and Male Fertility Requires the SHP2 Protein Tyrosine Phosphatase

Authors

  • Pawan Puri,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Bart T. Phillips,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Hitomi Suzuki,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Kyle E. Orwig,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Aleksandar Rajkovic,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Philip E. Lapinski,

    1. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Philip D. King,

    1. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Gen-Sheng Feng,

    1. Department of Pathology and Division of Biological Sciences, University of California, San Diego School of Medicine, San Diego, La Jolla, California, USA
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  • William H. Walker

    Corresponding author
    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Research in Reproductive Physiology, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    • Correspondence: William H. Walker, Ph.D., Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, 204 Craft Avenue, Room B305, Pittsburgh, Pennsylvania 15261, USA. Telephone: 412-641-7672; Fax: 412-641-7676; e-mail: walkerw@pitt.edu

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Abstract

SHP2 is a widely expressed protein tyrosine phosphatase required for signal transduction from multiple cell surface receptors. Gain and loss of function SHP2 mutations in humans are known to cause Noonan and LEOPARD syndromes, respectively, that are characterized by numerous pathological conditions including male infertility. Using conditional gene targeting in the mouse, we found that SHP2 is required for maintaining spermatogonial stem cells (SSCs) and the production of germ cells required for male fertility. After deleting SHP2, spermatogenesis was halted at the initial step during which transit-amplifying undifferentiated spermatogonia are produced from SSCs. In the absence of SHP2, proliferation of SSCs and undifferentiated spermatogonia was inhibited, thus germ cells cannot be replenished and SSCs cannot undergo renewal. However, germ cells beyond the undifferentiated spermatogonia stage of development at the time of SHP2 knockout were able to complete their maturation to become sperm. In cultures of SSCs and their progeny, inhibition of SHP2 activity reduced growth factor-mediated intracellular signaling that regulates SSC proliferation and cell fate. Inhibition of SHP2 also decreased the number of SSCs present in culture and caused SSCs to detach from supporting cells. Injection of mice with an SHP2 inhibitor blocked the production of germ cells from SSCs. Together, our studies show that SHP2 is essential for SSCs to maintain fertility and indicates that the pathogenesis of infertility in humans with SHP2 mutations is due to compromised SSC functions that block spermatogenesis. Stem Cells 2014;32:741–753

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