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Complete in vitro generation of fertile oocytes from mouse primordial germ cells

  1. Yayoi Obataa,1
  1. aDepartment of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan;
  2. bNODAI Genome Research Center, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan;
  3. cDepartment of Developmental Stem Cell Biology, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan;
  4. dJapan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Higashi-ku, Fukuoka 812-8582, Japan;
  5. eDivision of Animal Breeding and Reproduction Research, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki 305-0901, Japan
  1. Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved June 6, 2016 (received for review March 7, 2016)

Significance

Throughout the life of female mammals, only a small number of viable oocytes are produced. The mechanisms underlying the creation and selection of competent oocytes remain unclear. Here, we propose a novel approach for elucidating these unsolved questions, involving the use of an in vitro system established in the present study, which can fully reproduce mammalian oogenesis from mouse fetal primordial germ cells. Reconstitution of the entire oogenesis process has not been previously accomplished. Our system will assist in understanding the mechanisms of oogenesis and also create a new gamete resource in mammals.

Abstract

Reconstituting gametogenesis in vitro is a key goal for reproductive biology and regenerative medicine. Successful in vitro reconstitution of primordial germ cells and spermatogenesis has recently had a significant effect in the field. However, recapitulation of oogenesis in vitro remains unachieved. Here we demonstrate the first reconstitution, to our knowledge, of the entire process of mammalian oogenesis in vitro from primordial germ cells, using an estrogen-receptor antagonist that promotes normal follicle formation, which in turn is crucial for supporting oocyte growth. The fundamental events in oogenesis (i.e., meiosis, oocyte growth, and genomic imprinting) were reproduced in the culture system. The most rigorous evidence of the recapitulation of oogenesis was the birth of fertile offspring, with a maximum of seven pups obtained from a cultured gonad. Moreover, cryopreserved gonads yielded functional oocytes and offspring in this culture system. Thus, our in vitro system will enable both innovative approaches for a deeper understanding of oogenesis and a new avenue to create and preserve female germ cells.

Footnotes

  • ?1To whom correspondence may be addressed. Email: yujih{at}affrc.go.jp or y1obata{at}nodai.ac.jp.
  • Author contributions: K.H., Y.H., and Y.O. designed research; K.M., R.T., K.S., Y.H., and Y.O. performed research; R.K.-M. and T.K. contributed new reagents/analytic tools; K.M., R.T., and K.S. analyzed data; and K.M., K.H., Y.H., and Y.O. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1603817113/-/DCSupplemental.

Freely available online through the PNAS open access option.

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