PRIORITY PAPER EVALUATION – Talbot &

10.2217/17460751.1.5.xxx © 2 oo f Evaluation of: Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 1109–1114 (2006) [5]. This interesting study investigates the hypothesis that stem cells in adult bone marrow and the circulatory system populate mouse ovaries and contribute to the germline. When pairs of GFP+ and GFPparabiotic mice with joined circulatory systems were superovulated after 8 months of parabiosis, oocytes collected from the oviducts had the phenotype of the animal from which they had come. Follow-up experiments, in which oocytes were chemically destroyed before establishing parabiosis, yielded similar results. Injection of GFP+ or GFPbone marrow cells into mice with ovaries ablated using ovotoxins or irradiation did not rescue production of ovulated oocytes. These data do not support the controversial hypothesis that bone marrow stem cells contribute to the germline of adult female mice. uth or Pr For over 50 years, the idea that mammalian ovaries contain a finite number of oocytes at birth has been a dogma [1]. This concept was seriously challenged in 2004, when Jonathan Tilly’s laboratory at Harvard University (MA, USA) demonstrated that mouse ovaries may renew their supply of oocytes during adulthood [2]. Using a combination of experimental approaches, Tilly’s group concluded that mouse ovaries would run out of oocytes owing to atresia shortly after entering puberty if the population were not replenished. In a follow-up study, Tilly’s group went on to show that, if oocytes were chemically destroyed, intravenous injection of bone marrow cells from adult females resulted in the appearance of several hundred small follicles that presumably came from stem cells in the bone marrow transplant. Mice with a targeted disruption in the ataxia telangiectasia gene, which are sterile and have few if any oocytes, also acquired follicles following bone marrow transplants or injection of peripheral blood cells. In the peripheral blood rescue experiment, some follicles with green fluorescent protein (GFP)-positive oocytes, indicative of blood cell incorporation into the ovary, were observed within 24 h of the transplants. These findings were so unorthodox that numerous reviews immediately challenged the concepts conveyed in the Tilly papers (e.g., [3,4]). Follow-up studies in other laboratories on this interesting discovery have been slow in coming. However, this June, a publication addressing oocyte renewal in mice was published in Nature [5]. This ingenious study from Amy Wagers’ laboratory (also at Harvard University) used the interesting method of parabiosis, in which a pair of mice share their circulatory systems, to determine if circulating stem cells could pass between mice, colonize ovaries and develop into ovulated oocytes. One mouse in each parabiotic pair was transgenic for GFP, which it expressed in every cell, while the other mouse was wild-type, without any GFP expression. If stem cells from the bone marrow could enter the peripheral circulation and be transferred between animals and if these stem cells could be incorporated into the ovary and develop into oocytes, one would expect to see GFP+ oocytes in wild mice and GFPoocytes in transgenic females. To assay for stem cell transfer to ovaries, Wagers’ laboratory induced superovulation in females, collected oocytes from the oviduct and assessed them for chimerism using fluorescent microscopy.