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Title: ETS2 regulation of tissue size in early mouse embryogenesis
Author: Hu, Di
ISNI:       0000 0004 7971 6262
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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ETS2 is a transcription factor with both oncogenic and tumour suppressive roles, yet the mechanisms underlying these opposing effects remain unclear. I have analysed an Ets2- loss-of-function mouse mutant that displays a diminished extra-embryonic ectoderm (ExE) on one hand and a thickened anterior visceral endoderm (AVE) on the other. The opposing effects of ETS2 on tissue size, relevant to its tumour suppressive and oncogenic properties, appear to manifest in this mutant. Here I showed that the ExE defect is due to increased peri-implantation apoptosis, verified by phenotypic rescue via apoptosis inhibition. I demonstrated that the AVE transforms from a simple to stratified epithelium due to increased proliferation and perpendicular cell divisions, reminiscent of neoplastic transformation. Inhibition of MEK, which acts upstream of ETS2, phenocopied the AVE defect in wild type (WT) embryos. To identify ETS2 transcriptional targets that cause these AVE defects, I conducted single-cell RNA-sequencing (scRNA-seq), which showed that all cell types in the Ets2-mutant retain normal character; and revealed upregulation of several WNT/β-CATENIN pathway agonists in the mutant AVE. Pharmacological activation of the WNT/β-CATENIN pathway in WT recapitulated the mutant AVE phenotype, supporting scRNA-seq results. 2C-HR-CRIPSR mediated misexpression of candidate WNT agonists in the VE of WT embryos was attempted to verify whether the novel ETS2-WNT axis of AVE tissue size regulation is relevant in vivo. Overall, I have demonstrated the opposing effects of ETS2 on tissue size in early mouse embryogenesis: ETS2 protects the peri-implantation ExE from apoptosis, while dampens WNT/β-CATENIN signalling in the AVE to prevent overproliferation and maintain simple epithelial integrity.
Supervisor: Srinivas, Shankar Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available