STAT3 signaling enhances tissue expansion during postimplantation mouse development
Takuya Azami,
Bart Theeuwes,
Mai-Linh Nu Ton,
William Mansfield,
Luke Harland,
Masaki Kinoshita,
Berthold Gottgens,
Jennifer Nichols
Affiliations
Takuya Azami
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK; Corresponding author
Bart Theeuwes
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
Mai-Linh Nu Ton
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
William Mansfield
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
Luke Harland
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
Masaki Kinoshita
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
Berthold Gottgens
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK
Jennifer Nichols
Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 3EG, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Corresponding author
Summary: 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.
