A Mesodermal Factor, T, Specifies Mouse Germ Cell Fate by Directly Activating Germline Determinants

Germ cells ensure reproduction and heredity. In mice, primordial germ cells (PGCs), the precursors for spermatozoa and oocytes, are induced in pluripotent epiblast by BMP4 and WNT3, yet the underlying mechanism remains unclear. Here, using an in vitro PGC specification system, we show that WNT3 induces many transcription factors associated with mesoderm in epiblast-like cells through beta-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14 and directly upregulates these genes, delineating the downstream PGC program. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating a permissive role of BMP4 in PGC specification. These findings establish the key signaling mechanism for, and a fundamental role of a mesodermal factor in, mammalian PGC specification.