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Here, we establish rosette-formative intermediate stem cells (rfISCs) from mouse embryonic stem cells using the MEK inhibitor PD0325901, the Wnt inhibitor IWR1, and the PKA activator Forskolin. These cells exhibit transcriptomic\/epigenetic profiles mirroring those of E5.0\u20125.5 epiblasts, bridging rosette-stage and formative pluripotency. rfISCs demonstrate developmental bipotency, retaining in vitro germline differentiation capacity while generating germline-competent chimeras in vivo. Mechanistically, we identified opposing signaling axes that govern rfISC identification through the regulation of lineage priming: IWR1 stabilizes Tcf7l1 to drive Otx2-mediated rfISC specification and neural priming, whereas Forskolin activates PKA to induce Id1-dependent neural suppression. This creates a bistable regulatory circuit in which Otx2\/Id1 synergy maintains pluripotency plasticity under MEK inhibition. Notably, rfISCs can be directly derived from E5.25 epiblasts, confirming their physiological relevance. Our work bridges a fundamental gap in pluripotency modeling by capturing the RSC-to-FSC transition through dynamic signaling equilibria.<\/jats:p>","DOI":"10.1083\/jcb.202504054","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T07:21:06Z","timestamp":1772522466000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Bistable Otx2\u2013Id1 circuitry governs a developmental transition state in the pluripotency continuum"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3080-7160","authenticated-orcid":true,"given":"Peng","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05th6yx34","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Stem Cell and Translational Medicine, School of Life Sciences and Medical Engineering, Anhui University 1 , 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