Esrrb Complementation Rescues Development of Nanog-Null Germ Cells

Man Zhang,Harry G Leitch,Walfred W.C Tang,Nicola Festuccia,Elisa Hall-Ponsele,Jennifer Nichols,M Azim Surani,Austin Smith,Ian Chambers

doi:10.1016/j.celrep.2017.12.060

Abstract

SummaryThe 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.

Highlights

Naive pluripotency is established in epiblast cells of the mouse blastocyst (Boroviak et al, 2014; Brook and Gardner, 1997)
We show that germline deletion of Nanog reduces primordial germ-cell (PGC) numbers 5-fold at midgestation
Induced expression of Esrrb restores PGC-like cell (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

Summary

Graphical Abstract

Transcription factors functional in naive pluripotent cells are expressed in primordial germ cells (PGCs), their PGC role remains unclear. 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. Highlights d Germline deletion of Nanog reduces PGC numbers but does not abolish PGC development d Without Nanog, PGCLCs form ineffectively with less proliferation and more apoptosis d The Nanog target gene Esrrb can rescue PGCLC differentiation of NanogÀ/À ESCs d Knockin of Esrrb at the Nanog locus restores PGC development efficiency. 2018, Cell Reports 22, 332–339 January 9, 2018 a 2017 The Author(s).

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