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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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)
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)
Johnson, J. et al. Setting the record straight on data supporting postnatal oogenesis in female mammals. Cell Cycle 4, 1471–1477 (2005)
Telfer, E. E. et al. On regenerating the ovary and generating controversy. Cell 122, 821–822 (2005)
Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998)
Bunster, E. & Meyer, R. K. An improved method of parabiosis. Anat. Rec. 57, 339–343 (1933)
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)
Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005)
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)
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)
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)
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)
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)
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)
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)
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)
Byskov, A. G., Faddy, M. J., Lemmen, J. G. & Andersen, C. Y. Eggs forever? Differentiation 73, 438–446 (2005)
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)
Peters, H., Levy, E. & Crone, M. DNA synthesis in oocytes of mouse embryos. Nature 195, 915–916 (1962)
Zuckerman, S. The number of oocytes in the mature ovary. Recent Prog. Horm. Res. 6, 63–108 (1951)
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)
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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Chimerism of hematopoietic cells and ovulated oocytes in long-term parabiotic mice. (DOC 24 kb)
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)
GFP+ cells associated with ovulated oocytes are hematopoietic. (PDF 279 kb)
Ovarian damage induced by Cy/Bu is incomplete. (PDF 874 kb)
GFP+ cells associated with ovulated oocytes are hematopoietic. (PDF 261 kb)
Text to accompany the above Supplementary Figures. (DOC 25 kb)
About this article
Cite this article
Eggan, K., Jurga, S., Gosden, R. et al. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 1109–1114 (2006). https://doi.org/10.1038/nature04929