PT - JOURNAL ARTICLE AU - Kojima, Yoji AU - Yamashiro, Chika AU - Murase, Yusuke AU - Yabuta, Yukihiro AU - Okamoto, Ikuhiro AU - Iwatani, Chizuru AU - Tsuchiya, Hideaki AU - Nakaya, Masataka AU - Tsukiyama, Tomoyuki AU - Nakamura, Tomonori AU - Yamamoto, Takuya AU - Saitou, Mitinori TI - GATA transcription factors, SOX17 and TFAP2C, drive the human germ-cell specification program AID - 10.26508/lsa.202000974 DP - 2021 May 01 TA - Life Science Alliance PG - e202000974 VI - 4 IP - 5 4099 - https://www.life-science-alliance.org/content/4/5/e202000974.short 4100 - https://www.life-science-alliance.org/content/4/5/e202000974.full SO - Life Sci. Alliance2021 May 01; 4 AB - The in vitro reconstitution of human germ-cell development provides a robust framework for clarifying key underlying mechanisms. Here, we explored transcription factors (TFs) that engender the germ-cell fate in their pluripotent precursors. Unexpectedly, SOX17, TFAP2C, and BLIMP1, which act under the BMP signaling and are indispensable for human primordial germ-cell-like cell (hPGCLC) specification, failed to induce hPGCLCs. In contrast, GATA3 or GATA2, immediate BMP effectors, combined with SOX17 and TFAP2C, generated hPGCLCs. GATA3/GATA2 knockouts dose-dependently impaired BMP-induced hPGCLC specification, whereas GATA3/GATA2 expression remained unaffected in SOX17, TFAP2C, or BLIMP1 knockouts. In cynomolgus monkeys, a key model for human development, GATA3, SOX17, and TFAP2C were co-expressed exclusively in early PGCs. Crucially, the TF-induced hPGCLCs acquired a hallmark of bona fide hPGCs to undergo epigenetic reprogramming and mature into oogonia/gonocytes in xenogeneic reconstituted ovaries. By uncovering a TF circuitry driving the germ line program, our study provides a paradigm for TF-based human gametogenesis.