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Ovulated oocytes in adult mice derive from non-circulating germ cells


Decades of research in reproductive biology have led to the generally accepted belief that in female mammals, all surviving germ cells enter meiosis at the end of fetal development and as a result, the postnatal ovary harbours a limited supply of oocytes that cannot be replenished or regenerated if lost to injury or disease. However, recent reports have challenged this view, suggesting instead that oocyte production is maintained through continual seeding of the ovary by circulating, bone-marrow-derived germ cells. To test directly the physiological relevance of circulating cells for female fertility, we established transplantation and parabiotic mouse models to assess the capacity of circulating bone marrow cells to generate ovulated oocytes, both in the steady state and after induced damage. Our studies showed no evidence that bone marrow cells, or any other normally circulating cells, contribute to the formation of mature, ovulated oocytes. Instead, cells that travelled to the ovary through the bloodstream exhibited properties characteristic of committed blood leukocytes.

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Figure 1: Circulating cells do not give rise to mature oocytes in long-term parabionts.
Figure 2: Circulating cells do not give rise to mature oocytes in injured parabionts.
Figure 3: Bone marrow cells do not give rise to oocytes and do not enhance ovulation of endogenous oocytes in transplanted mice.

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  1. Johnson, J., Canning, J., Kaneko, T., Pru, J. K. & Tilly, J. L. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145–150 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Johnson, J. et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 122, 303–315 (2005)

    Article  CAS  PubMed  Google Scholar 

  3. Johnson, J. et al. Setting the record straight on data supporting postnatal oogenesis in female mammals. Cell Cycle 4, 1471–1477 (2005)

    Article  CAS  PubMed  Google Scholar 

  4. Telfer, E. E. et al. On regenerating the ovary and generating controversy. Cell 122, 821–822 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998)

    CAS  PubMed  Google Scholar 

  6. Bunster, E. & Meyer, R. K. An improved method of parabiosis. Anat. Rec. 57, 339–343 (1933)

    Article  Google Scholar 

  7. Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Sherwood, R. I., Christensen, J. L., Weissman, I. L. & Wagers, A. J. Determinants of skeletal muscle contribution from circulating cells, bone marrow cells, and hematopoietic stem cells. Stem Cells 22, 1292–1304 (2004)

    Article  PubMed  Google Scholar 

  10. Wagers, A. J., Sherwood, R. I., Christensen, J. L. & Weissman, I. L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. “Green mice” as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

    Article  CAS  PubMed  Google Scholar 

  12. Shiromizu, K., Thorgeirsson, S. S. & Mattison, D. R. Effect of cyclophosphamide on oocyte and follicle number in Sprague-Dawley rats, C57BL/6N and DBA/2N mice. Pediatr. Pharmacol. 4, 213–221 (1984)

    CAS  Google Scholar 

  13. Burkl, W. & Schiechl, H. The growth of follicles in the rat ovary under the influence of busulphan and endoxan. Cell Tissue Res. 186, 351–359 (1978)

    Article  CAS  PubMed  Google Scholar 

  14. Mattison, D. R., Chang, L., Thorgeirsson, S. S. & Shiromizu, K. The effects of cyclophosphamide, azathioprine, and 6-mercaptopurine on oocyte and follicle number in C57BL/6N mice. Res. Commun. Chem. Pathol. Pharmacol. 31, 155–161 (1981)

    CAS  PubMed  Google Scholar 

  15. Meirow, D., Epstein, M., Lewis, H., Nugent, D. & Gosden, R. G. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum. Reprod. 16, 632–637 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Bhattacharya, D., Rossi, D. J., Bryder, D. & Weissman, I. L. Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning. J. Exp. Med. 203, 73–85 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Byskov, A. G., Faddy, M. J., Lemmen, J. G. & Andersen, C. Y. Eggs forever? Differentiation 73, 438–446 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. Franchi, L. L., Mandl, A. M. & Zuckerman, S. The Development of the Ovary and the Process of Oogenesis (ed. Zuckerman, S.) (Academic Press, New York, 1962)

    Google Scholar 

  19. Peters, H., Levy, E. & Crone, M. DNA synthesis in oocytes of mouse embryos. Nature 195, 915–916 (1962)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Zuckerman, S. The number of oocytes in the mature ovary. Recent Prog. Horm. Res. 6, 63–108 (1951)

    Google Scholar 

  21. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001)

    Article  CAS  PubMed  Google Scholar 

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The authors wish to thank J. LaVecchio and the Joslin Diabetes Center DERC and HSCI Flow Cytometry Cores for FACS analysis, J. O'Keefe for animal management, J. Stockton for provision of the dissecting microscope, C. Lesser for helpful comments, and D. Mathis, D. Egli and E. Trish for critical reading of the manuscript. This work was supported in part by a Burroughs Wellcome Fund Career Award to A.J.W., and NIH grants to I.M.M. and K.E. Author Contributions A.J.W., K.E. and R.G. designed the experiments. A.J.W. performed parabiosis surgeries and transplantations, collected tissues, and analysed haematopoietic chimaerism. K.E. collected oocytes and analysed oocyte chimaerism. I.M.M. and S.J. assisted with flow cytometry and tissue analysis. A.J.W. and K.E. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Amy J. Wagers.

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Supplementary information

Supplemental Table 1

Chimerism of hematopoietic cells and ovulated oocytes in long-term parabiotic mice. (DOC 24 kb)

Supplemental Table 2

Chimerism of hematopoietic cells and ovulated oocytes in parabiotic mice pre-treated with the germ cell toxins cyclophosphamide (Cy) and busulfan (Bu). (DOC 24 kb)

Supplemental Figure 1

GFP+ cells associated with ovulated oocytes are hematopoietic. (PDF 279 kb)

Supplemental Figure 2

Ovarian damage induced by Cy/Bu is incomplete. (PDF 874 kb)

Supplemental Figure 3

GFP+ cells associated with ovulated oocytes are hematopoietic. (PDF 261 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures. (DOC 25 kb)

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Eggan, K., Jurga, S., Gosden, R. et al. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 1109–1114 (2006).

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