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Gene Expression Dynamics During Germline Specification in Mice Identified by Quantitative Single-Cell Gene Expression Profiling¹

Laboratory for Mammalian Germ Cell Biology,⁴ Center for Developmental Biology, RIKEN Kobe Institute, Kobe 650-0047, Japan Precursory Research for Embryonic Science and Technology,⁵ Japan Science and Technology Agency, Saitama 332-0012, Japan Laboratory of Molecular Cell Biology and Development,⁶ Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan

ABSTRACT

Germ cell fate in mice is induced in proximal epiblast cells at Embryonic Day (E) 6.5 by signaling molecules. Prdm1(also known as Blimp1)-positive lineage-restricted precursors of primordial germ cells (PGCs) initiate the formation of a cluster that differentiates into Dppa3 (also known as stella)-positive PGCs from around E7.0 onwards in the extra-embryonic mesoderm. Around E7.5, these PGCs begin migrating towards the definitive endoderm, with concomitant extensive epigenetic reprogramming. To gain a more precise insight into the mechanism of PGC specification and its subsequent development, we exploited quantitative, single-cell, gene expression profiling to explore gene expression dynamics during the 36 h of PGC differentiation from E6.75 to E8.25, in comparison with the corresponding profiles of somatic neighbors. This analysis revealed that the transitions from Prdm1-positive PGC precursors to Dppa3-positive PGCs and to more advanced migrating PGCs involve a highly dynamic, stage-dependent transcriptional orchestration that begins with the regaining of the pluripotency-associated gene network, followed by stepwise activation of PGC-specific genes, differential repression of the somatic mesodermal program, as well as potential modulations of signal transduction capacities and unique control of epigenetic regulators. The information presented here regarding the cascade of events involved in PGC development should serve as a basis for detailed functional analyses of the gene products associated with this process, as well as for appropriate reconstitution of PGCs and their descendant cells in culture.

developmental biology, early development, embryo, gamete biology, gene regulation

² Correspondence: Mitinori Saitou, Laboratory for Mammalian Germ Cell Biology, Center for Developmental Biology, RIKEN Kobe Institute, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan. FAX: 81 78 306 3377; saitou{at}cdb.riken.jp

³ These authors contributed equally to this work.

¹ Supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a PRESTO project grant from the Japan Science and Technology Agency.

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