Related Experiment Video
Updated: Jun 4, 2026
10:19
Derivation of Mouse Trophoblast Stem Cells from Blastocysts
Published on: June 8, 2010
Replication stress primes a trophectoderm fate in embryonic stem cells
Andrea Gnocchi1,2, Christelle El Kai2, Cristina Castellan1,2
1Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy.
Cell Death Discovery
|June 2, 2026
Summary
Replication stress during early development drives embryonic stem cells toward trophoectoderm fate via ATR and JNK signaling. This stress-induced lineage plasticity persists, impacting extraembryonic development and potentially adult cell identity.
Area of Science:
- Developmental Biology
- Cellular Stress Response
- Epigenetics
Background:
- Early embryogenesis involves rapid cell cycles, leading to significant replication stress (RS).
- The impact of RS on embryonic cell lineage potential is not well understood.
- Mouse embryonic stem cells (ESCs) serve as a model for the inner cell mass.
Purpose of the Study:
- To investigate how replication stress (RS) influences lineage potential in mouse ESCs.
- To elucidate the molecular pathways mediating RS-induced cell fate changes.
- To determine if RS-induced lineage bias persists after stress withdrawal.
Main Methods:
- Utilized mouse ESCs as an in vitro model for early embryogenesis.
- Applied replication stress (RS) to ESCs and monitored gene expression changes.
- Inhibited ATR and JNK signaling pathways to assess their roles in RS-induced responses.
- Performed quantitative chromatin proteomics to analyze molecular changes.
- Assessed ESC contribution to extraembryonic compartments in embryo-like structures.
Main Results:
- RS rapidly and durably induced trophoectoderm (TE) regulators (Cdx2, Gata3, Eomes, Elf5, Hand1, Tfap2c).
- ATR checkpoint signaling was required for RS-induced TE gene expression; ATR inhibition did not restore pluripotency.
- JNK activation and subsequent c-JUN phosphorylation by RS contributed to TE induction.
- The TE bias persisted post-stress, promoting TE-like phenotypes and enhancing ESC contribution to extraembryonic tissues.
- Chromatin analysis showed nucleosome and condensin eviction, with enrichment of DNA repair factors and ATR cofactors.
Conclusions:
- An ATR- and JNK/c-JUN-dependent stress response axis redirects embryonic cell identity toward TE, linking RS to developmental plasticity.
- RS actively drives cell fate decisions rather than causing passive identity loss.
- The observed lineage plasticity, if reactivated in adults, could influence somatic cell fate and potentially predispose to malignancy.
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