ETV4 is a mechanical transducer linking cell crowding dynamics to lineage specification

“…Etv4 is a known downstream target of glial cell line-derived neurotrophic factor (GDNF) signaling in kidney development ( Lu et al, 2009 ) and fibroblast growth factor (FGF) signaling in limb development ( Mao et al, 2009 ). It plays a critical role in FGF-extracellular signal regulated kinase (ERK) signaling in pluripotent cells ( Akagi et al, 2015 ; Simon et al, 2024 ; Yang et al, 2024 ). However, during P14BA-rPGCLC induction, replacing AC with FGF2 fails to induce PGCLCs ( Figure S3 G), suggesting a context-dependent relationship between external signals and transcriptional regulators.…”

“…From our candidate screening, we identified Etv4 as a downstream target of Activin and WNT signals. A recent report showed that the expression of ETV4 varies depending on the size of human PSC colonies and its expression connects cell crowding with lineage specification ( Yang et al, 2024 ). ETV4 positive cells located at the colony edges exhibit mesendodermal fate, while ETV4 negative areas in the colony center are associated with neuroectodermal fate ( Yang et al, 2024 ).…”

“…It called our attention that three NSC-associated genes were commonly downregulated in DNp73KO and TAp73KO-mBOs both at day 7 and 14: NADPH-Dependent Carbonyl Reductase 3 ( Cbr3 ), Thiosulfate Sulfurtransferase ( Tst ) and ETS Variant Transcription Factor 4 ( Etv4 ). The downregulation of Etv4 is of particular interest, since it works as a mechanical transducer that drives spatiotemporal lineage specification and its inactivation in human embryonic stem cell epithelia derepresses the neuroectoderm fate ( Yang et al, 2024 ). On the other hand, DNp73KO-mBOs remarkably upregulated genes related to the neural fate when compared to the WT counterparts, whereas the lack of TAp73 had a milder outcome.…”

“…To investigate the role of prolonged crowding in tumor invasion, we employed a spontaneous crowding model 20 using HeLa cells, which were allowed to freely grow as a monoclonal cell sheet for 14 days (Fig. 1a).…”