Grhl2-regulation of Developing Ectoderm as a Model to Identify Suppressors of EMT

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): The epithelial-to-mesenchymal (EMT) transition plays an essential role during embryonic development. Studies have also found that EMT can be involved in the promotion of various epithelial cancers. Recent evidence supports the idea that the EMT process between development and cancer is similar at the molecular level. Therefore, using an in vivo developmental system to study how EMT is regulated may identify genes that are relevant targets for treatment of human cancers. During embryonic neural tube closure, neural crest cells undergo an EMT as they delaminate out of the neuroectoderm to migrate to distant sites. At the same time, the neighboring non-neural ectoderm (NNE) cells must remain tightly associated within the same epithelium in order for neural tube closure to proceed correctly. Much is known about the regulatory mechanisms driving neural crest EMT, however less is known about how the non-neural ectoderm enforces its epithelial fate. The transcription factor Graineyhead like 2 (Grhl2) is expressed within the NNE cells during neural tube closure and may act as a suppressor of EMT via its direct downstream targets. In fact, GRHL2 has recently been shown to act in this manner in a breast cancer model. Isolation of NNE from embryos at the time of neural tube closure followed by high throughput RNA-sequencing led to the identification of several genes that may be involved in EMT suppression in this tissue. In this project, a loss of function Grhl2 mouse model (Grhl21Nisw/1Nisw) will be used to explore these genes for a potential role within a Grhl2-regulated network of EMT suppression in the NNE of the mouse embryo. Further assessment of these genes will show how loss of gene function affects the dynamics of NNE cell behavior during neural tube closure. Genes that are found to suppress EMT in the developing neural tube will then be further investigated in a breast cancer model to determine if they affect both in vitro EMT as well as in vivo metastasis. Through this study, a further understanding of a Grhl2- regulated gene network of EMT suppression will be gained and targets may be identified that could impact the progression of epithelial cancers.