BMP4 activates the Wnt-Lin28A-Blimp1-Wnt pathway to promote primordial germ cells formation via altering H3K4me2.

The unique developmental characteristics of Chicken primordial germ cells (PGCs) enable it to be used in recovery of endangered bird species, gene editing and the generation of transgenic birds, but the limited number of PGCs greatly limits its application. Studies have shown that the formation of mammalian PGCs is induced by BMP4 signal, but the formation mechanism of chicken PGCs has not been determined. Here, we confirmed that Wnt signaling activated via BMP4 activates transcription of Lin28A by inducing β-catenin to compete with LSD1 for binding to TCF7L2, causing LSD1 to dissociate from the Lin28A promoter and enhanced H3K4me2 methylation in this region. Lin28A promotes PGCs formation by inhibiting gga-let7a-3p maturation to initiate Blimp1 expression. Interestingly, expression of Blimp1 helped sustain Wnt5A expression by preventing LSD1 binding to the Wnt5A promoter. We thus elucidated a positive feedback pathway involving Wnt-Lin28-Blimp1-Wnt, that ensures PGCs formation. In summary, our data provide a new insights in the development of PGCs in chickens.