The current status of evidence for and against postnatal oogenesis in mammals: a case of ovarian optimism versus pessimism?

Abstract

Whether or not oogenesis continues in the ovaries of mammalian females during postnatal life was heavily debated from the late 1800s through the mid-1900s. However, in 1951 Lord Solomon Zuckerman published what many consider to be a landmark paper summarizing his personal views of data existing at the time for and against the possibility of postnatal oogenesis. In Zuckerman's opinion, none of the evidence he considered was inconsistent with Waldeyer's initial proposal in 1870 that female mammals cease production of oocytes at or shortly after birth. This conclusion rapidly became dogma, and remained essentially unchallenged until just recently, despite the fact that Zuckerman did not offer a single experiment proving that adult female mammals are incapable of oogenesis. Instead, 20 years later he reemphasized that his conclusion was based solely on an absence of data he felt would be inconsistent with the idea of a nonrenewable oocyte pool provided at birth. However, in the immortal words of Carl Sagan, an "absence of evidence is not evidence of absence." Indeed, building on the efforts of a few scientists who continued to question this dogma after Zuckerman's treatise in 1951, we reported several data sets in 2004 that were very much inconsistent with the widely held belief that germ cell production in female mammals ceases at birth. Perhaps not surprisingly, given the magnitude of the paradigm shift being proposed, this work reignited a vigorous debate that first began more than a century ago. Our purpose here is to review the experimental evidence offered in recent studies arguing support for and against the possibility that adult mammalian females replenish their oocyte reserve. "Never discourage anyone who continually makes progress, no matter how slow."-Plato (427-347 BC).

FIG. 1.

Parabiosis reveals the presence of circulating germline progenitor cells in adult female mice that can form immature (primordial) oocytes. After initiating parabiosis between 2-mo-old wild-type and TgOG2 transgenic females (left; bottom images are from positive and negative controls showing EGFP detection in ovarian sections from TgOG2 and wild-type mice, respectively, prior to parabiosis; see Lee et al. [72] for more details), EGFP-positive immature oocytes enclosed within follicles can be readily detected in the ovaries of wild-type partners within 4 wk of joining (right; data shown are from ovaries of three different mice). Black arrows highlight examples of TgOG2-derived (EGFP-positive; brown) immature oocytes in the ovaries of the wild-type females, whereas white arrows demarcate adjacent wild-type oocytes of approximately the same maturational status. This experiment was reviewed and approved by the institutional animal care and use committee of Massachusetts General Hospital. Original magnification ×40.

FIG. 2.

Detection of immature oocytes in ovarian tissue sections of mice by histological approaches and by the use of a transgenic reporter with germline-specific expression of EGFP. A–C) Photomicrographs of oocyte-containing immature follicles in adult mouse ovaries, showing examples of nonatretic primordial (B; arrowheads in A), primary (C; arrow in A), and preantral (asterisk in A) follicles. Original magnifications ×20 (A), ×60 (B), and ×40 (C). D) Use of immunohistochemistry to demonstrate the restricted expression of EGFP (brown immunostaining; see Lee et al. [72] for methodological details) in the oocytes of adult TgOG2 females (arrowheads demarcate primordial oocytes; see also Fig. 1). The ovarian section was counterstained with hematoxylin to visualize tissue architecture. E) Direct fluorescence analysis of EGFP expression (green fluorescence) in ovaries of adult TgOG2 females after counterstaining with a nuclear dye to highlight tissue architecture (blue fluorescence). Two EGFP-positive immature oocytes are shown. Past studies [40] have demonstrated that EGFP-positive oocytes derived from TgOG2 animals coexpress well-accepted markers of the germline (MVH) and of oocytes (NOBOX, GDF-9). This experiment was reviewed and approved by the institutional animal care and use committee of Massachusetts General Hospital. Original magnifications ×20 (D) and ×40 (E).