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Epithelial to mesenchymal transition intermediate states in mammalian neural crest cell delamination
Zhao, Ruonan
Zhao, Ruonan
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Abstract
Epithelial to mesenchymal transition (EMT) is a cellular process that converts epithelial cells to mesenchymal cells with migratory potential. EMT is essential in both developmental and pathological events such as embryonic morphogenesis, tissue fibrosis and cancer. EMT in cancer progression has been shown to involve intermediate states that are characterized by distinct combinations of epithelial and mesenchymal features as well as corresponding changes in cytoarchitecture. However, EMT intermediate states remain poorly described and understood. Moreover, whether intermediate states are present in other EMT events is understudied during development. Neural crest cells (NCCs) are an embryonic progenitor cell population that gives rise to numerous cell types and tissues in vertebrates. One important feature of NCC development is the delamination of premigratory NCCs from the neuroepithelium via EMT, following which NCCs migrate throughout the embryo and undergo differentiation. NCC EMT shares similar changes in cellular structures with malignant cells as they invade into the surrounding environment. Therefore, NCC EMT provides a valuable tool to explore the molecular and cellular changes underlying intermediate states during developmental EMT. Identification of NCC EMT intermediate states will also facilitate our understanding of mammalian NCC delamination. Through single cell RNA sequencing and in vivo imaging, we have identified cranial NCC subpopulations that represent EMT intermediate stages between premigratory and migratory NCCs. Transcriptional knockdown reveals a functional role for the intermediate stage marker Dlc1 in regulating NCC delamination and migration. Additionally, cell cycle gene expression and trajectory analysis indicate that a majority of EMT intermediate NCCs delaminate in S phase or G2/M phase of the cell cycle independently prior to migration. Cell cycle inhibitor treatment further confirms that cell cycle regulation plays an essential role in facilitating mammalian cranial NCC delamination and EMT. In summary, the characterization of NCC EMT intermediate states has identified novel gene regulators and pathways underlying cranial NCC delamination in mammalian species. This work will also provide insights into the molecular mechanisms regulating pathological EMT.
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2023-05-31
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University of Kansas
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988007_1.pdf
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Keywords
Developmental biology, Cellular biology, Delamination, EMP, EMT, Mouse, Neural crest cells