GATA transcription factors, SOX17 and TFAP2C, drive the human germ-cell specification program

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, <i>SOX17</i>, <i>TFAP2C</i>, and <i>BLIMP1</i>, which act under the BMP signaling and are indispensable for human primordial germ-cell-like cell (hPGCLC) specification, failed to induce hPGCLCs. In contrast, <i>GATA3</i> or <i>GATA2</i>, immediate BMP effectors, combined with <i>SOX17</i> and <i>TFAP2C</i>, generated hPGCLCs. <i>GATA3</i>/<i>GATA2</i> knockouts dose-dependently impaired BMP-induced hPGCLC specification, whereas <i>GATA3</i>/<i>GATA2</i> expression remained unaffected in <i>SOX17</i>, <i>TFAP2C</i>, or <i>BLIMP1</i> knockouts. In cynomolgus monkeys, a key model for human development, <i>GATA3</i>, <i>SOX17</i>, and <i>TFAP2C</i> 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.