{ "abstract": "Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3’untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation. Author summary: Embryonic stem cells can give rise to every cell type in the body, but this requires precise regulation of gene expression as development progresses. Although much is known about how genes are turned on and off, less is understood about how cells fine-tune the messenger RNA (mRNA) transcripts to mold the final messages that make proteins. Here, we show that two distinct mRNA regulatory mechanisms cooperate to control expression of Profilin-2 (Pfn2), a gene expressed in early embryonic development. We found that neighboring binding sites for embryonic stem cell-enriched microRNAs and Iron Regulatory Proteins (IRPs) within the Pfn2 mRNA have different functions during development. Loss of the microRNA binding site increases PFN2 levels and disrupts the transition from pluripotency by reducing FGF signaling. In contrast, loss of the IRP binding site decreases PFN2 levels, impairs Wnt/β-catenin signaling, and blocks formation of the mesendoderm embryonic cell lineages. Together, our findings identify Pfn2 as a critical post-transcriptional regulatory node that coordinates successive developmental transitions and reveal how precise regulation of a single mRNA can determine cell fate during early embryonic development.", "abstract_shown": true, "affiliations": [ "Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America", "The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California, United States of America", "Department of Urology, University of California, San Francisco, San Francisco, California, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 4, "authors": [ { "affs": [ 0 ], "name": "Carolyn Sangokoya" }, { "affs": [ 1 ], "name": "Isabella R. Rosso" }, { "affs": [ 2 ], "name": "Rana Ghandehari-Alavijeh" }, { "name": "Robert Blelloch" } ], "bibtex": "https://research.draconitic.com/paper/73k8yhqhqxq2d.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012279", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012279", "id": "73k8yhqhqxq2d", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012279", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1306|MicroRNA in disease regulation" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Messenger RNA/Untranslated regions/3' UTR" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Natural antisense transcripts/MicroRNAs" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Stem cells/Cell potency/Pluripotency" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Wnt signaling cascade" ], [ "plos", "/Biology and life sciences/Developmental biology/Cell differentiation" ], [ "plos", "/Biology and life sciences/Developmental biology/Embryology/Mesoderm" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/MicroRNAs" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication/Internal ribosome entry site" ], [ "plos", "/Research and analysis methods/Spectrum analysis techniques/Spectrophotometry/Cytophotometry/Flow cytometry" ] ], "openalex": "W7206214383", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012279&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-02", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/73k8yhqhqxq2d.ris", "sources": [ { "first_seen": "2026-10-30T12:18:02Z", "native_id": "10.1371/journal.pgen.1012279", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012279" } ], "subjects": [ { "field": "biology", "origin": "plos:stem cells", "subfield": "developmental-biology" } ], "title": "Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions", "title_text": "Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:02Z", "url": "https://research.draconitic.com/paper/73k8yhqhqxq2d", "venue": "PLOS Genetics", "versions": [] }