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

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/nature04929

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