期刊
DEVELOPMENT
卷 138, 期 9, 页码 1827-1838出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.053645
关键词
Cranial neural crest; Craniofacial development; Epithelial-mesenchymal transition; EMT; p53; Mouse; Chick
资金
- Helen and Martin Kimmel Institute for Stem Cell Research
- Minerva Foundation
- Association Francaise Contre les Myopathies
- Israel Science Foundation
- German-Israel Foundation (GIF)
- United States-Israel Binational Science Foundation
Neural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear. We have investigated the role of p53 in early cranial neural crest (CNC) development in chick and mouse embryos. In the mouse, p53 knockout embryos displayed broad craniofacial defects in skeletal, neuronal and muscle tissues. In the chick, p53 is expressed in CNC progenitors and its expression decreases with their delamination from the neural tube. Stabilization of p53 protein using a pharmacological inhibitor of its negative regulator, MDM2, resulted in reduced SNAIL2 (SLUG) and ETS1 expression, fewer migrating CNC cells and in craniofacial defects. By contrast, electroporation of a dominant-negative p53 construct increased PAX7(+) SOX9(+) CNC progenitors and EMT/delamination of CNC from the neural tube, although the migration of these cells to the periphery was impaired. Investigating the underlying molecular mechanisms revealed that p53 coordinates CNC cell growth and EMT/delamination processes by affecting cell cycle gene expression and proliferation at discrete developmental stages; disruption of these processes can lead to craniofacial defects.
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