GATA transcription factors, SOX17 and TFAP2C, drive the human germ-cell specification program
Yoji Kojima, Chika Yamashiro, Yusuke Murase, Yukihiro Yabuta, Ikuhiro Okamoto, Chizuru Iwatani, Hideaki Tsuchiya, Masataka Nakaya, Tomoyuki Tsukiyama, Tomonori Nakamura, Takuya Yamamoto, Mitinori Saitou
Abstract
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.