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Tyro-3 family receptors are essential regulators of mammalian spermatogenesis

Nature volume 398, pages 723–728 (1999)Cite this article

Abstract

We have generated and analysed null mutations in the mouse genes encoding three structurally related receptors with tyrosine kinase activity: Tyro 3, Axl, and Mer1,4. Mice lacking any single receptor, or any combination of two receptors, are viable and fertile, but male animals that lack all three receptors produce no mature sperm, owing to the progressive death of differentiating germ cells. This degenerative phenotype appears to result from a failure of the tropic support that is normally provided by Sertoli cells of the seminiferous tubules, whose function depends on testosterone and additional factors produced by Leydig cells5,7. Tyro 3, Axl and Mer are all normally expressed by Sertoli cells during postnatal development, whereas their ligands, Gas6 and protein S, are produced by Leydig cells before sexual maturity, and by both Leydig and Sertoli cells thereafter. Here we show that the concerted activation of Tyro 3, Axl and Mer in Sertoli cells is critical to the role that these cells play as nurturers of developing germ cells. Additional observations indicate that these receptors may also be essential for the tropic maintenance of diverse cell types in the mature nervous, immune and reproductive systems.

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Figure 1: Inactivation of the mouse Tyro 3, Axl and Mer genes.
Figure 2: Aborted spermatogenesis and germ-cell death in seminiferous tubules of Tyro 3−/−Axl−/−Mer−/− mice.
Figure 3: Tyro 3 family receptors and their ligands in the testes.
Figure 4: Expression of GATA-1 in wild-type (+/+) and triple-mutant (tko) testes.

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Acknowledgements

This work was supported by grants from the NIH (to G.L., S.P.G., H.S.E., G.K.M.), and by a Markey fellowship to M.G., who was a student in the Neurosciences graduate program at the University of California, San Diego. S.P.G. is an Investigator of the Howard Hughes Medical Institute. We thank A. Prieto for advice and for Gas6 antibody, G. Yancopoulos for Gas6, protein S, and Axl cDNA probes, and D. Ortuño, P. Burrola, and D. Baynes for technical assistance.

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Author notes

  1. Martin Gore

    Present address: Arena Pharmaceuticals, San Diego, California, 92121, USA

  2. Qingxian Lu and Martin Gore: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, California, 92037, La Jolla, USA

    Qingxian Lu, Martin Gore & Greg Lemke

  2. Howard Hughes Medical Institute and Department of Biochemsitry,

    Qing Zhang

  3. Neuroscience Center and Department of Microbiology,

    Todd Camenisch & Glenn K. Matsushima

  4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hil, 27599, North Carolina, USA

    Stephen P. Goff

  5. Developmental Biology Programme, European Molecular Biology Laboratory, Heidelberg, 69117, Germany

    Sharon Boast, Franca Casagranda & Rüdiger Klein

  6. Department of Neuropharmacology, Scripps Research Institute, La Jolla, 92037, California, USA

    Cary Lai

  7. Department of Genetics and Cell Biology, Center for Reproductive Biology, Washington State University, Pullman, 99164, Washington, USA

    Michael K. Skinner

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Correspondence to Glenn K. Matsushima.

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Lu, Q., Gore, M., Zhang, Q. et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398, 723–728 (1999). https://doi.org/10.1038/19554

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