Esrrb Complementation Rescues Development of Nanog-Null Germ Cells

Summary The transcription factors (TFs) Nanog and Esrrb play important roles in embryonic stem cells (ESCs) and during primordial germ-cell (PGC) development. Esrrb is a positively regulated direct target of NANOG in ESCs that can substitute qualitatively for Nanog function in ESCs. Whether this functional substitution extends to the germline is unknown. Here, we show that germline deletion of Nanog reduces PGC numbers 5-fold at midgestation. Despite this quantitative depletion, Nanog-null PGCs can complete germline development in contrast to previous findings. PGC-like cell (PGCLC) differentiation of Nanog-null ESCs is also impaired, with Nanog-null PGCLCs showing decreased proliferation and increased apoptosis. However, induced expression of Esrrb restores PGCLC numbers as efficiently as Nanog. These effects are recapitulated in vivo: knockin of Esrrb to Nanog restores PGC numbers to wild-type levels and results in fertile adult mice. These findings demonstrate that Esrrb can replace Nanog function in germ cells.
Graphical Abstract
Highlights • Germline deletion of Nanog reduces PGC numbers but does not abolish PGC development • Without Nanog, PGCLCs form ineffectively with less proliferation and more apoptosis • The Nanog target gene Esrrb can rescue PGCLC differentiation of Nanog−/− ESCs • Knockin of Esrrb at the Nanog locus restores PGC development efficiency
Although transcription factors functional in naive pluripotent cells are also expressed in primordial germ cells (PGCs), their PGC role remains unclear. Here, Zhang et al. show that, without Nanog, PGCs form ineffectively but that normal PGC development can be restored by induced expression of the NANOG target gene Esrrb.