STAT3 signaling enhances tissue expansion during postimplantation mouse development

Azami, Takuya; Theeuwes, Bart; Ton, Mai-Linh Nu; Mansfield, William; Harland, Luke; Kinoshita, Masaki; Gottgens, Berthold; Nichols, Jennifer

Abstract

Signal transducer and activator of transcription (STAT)3 signaling has been studied extensively using mouse embryonic stem cells. Zygotic deletion of Stat3 enables embryo implantation, but thereafter, mutants resemble non-affected littermates from the previous day until around mid-gestation. This probably results from the loss of serine-phosphorylated STAT3, the predominant form in early postimplantation embryonic tissues associated with mitochondrial activity. Bulk RNA sequencing of isolated mouse epiblasts confirmed developmental delay transcriptionally. Single-cell RNA sequencing revealed the exclusion of derivatives of Stat3 null embryonic stem cells exclusively from the erythroid lineage of mid-gestation chimeras. We show that Stat3 null embryonic stem cells can differentiate into erythroid and hematopoietic lineages in vitro but become outcompeted when mixed with wild-type cells. Our results implicate a role for STAT3 in the temporal control of embryonic progression, particularly in tissues requiring rapid cell division, such as postimplantation epiblast and hematopoietic lineages. Interestingly, mutations in STAT3 are associated with short stature in humans.

Citation

Azami, T., Theeuwes, B., Ton, M.-L. N., Mansfield, W., Harland, L., Kinoshita, M., Gottgens, B., & Nichols, J. (2025). STAT3 signaling enhances tissue expansion during postimplantation mouse development. Cell Reports, 44(4), Article 115506. https://doi.org/10.1016/j.celrep.2025.115506

• Journal Article Type: Article
• Acceptance Date: Mar 12, 2025
• Online Publication Date: Apr 5, 2025
• Publication Date: Apr 22, 2025
• Deposit Date: Mar 20, 2025
• Publicly Available Date: Mar 20, 2025
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Electronic ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 44
• Issue: 4
• Article Number: 115506
• DOI: https://doi.org/10.1016/j.celrep.2025.115506
• Keywords: Chimeras, Developmental delay, Erythroid differentiation, Pluripotent stem cells, RNA sequencing, STAT3 signalling
• Public URL: https://nottingham-repository.worktribe.com/output/46738479
• Publisher URL: https://www.cell.com/cell-reports/fulltext/S2211-1247(25)00277-3