Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT
Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT
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DOI：
10.1073/pnas.1601252113
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Jianjian Zhu;K. Kwan;S. Mackem
中科院分区：
文献类型：
--
作者：
Jianjian Zhu;K. Kwan;S. Mackem
Significance The notochord is a rod of axial mesoderm that secretes signals that induce formation of vertebrae from somitic mesoderm during embryogenesis. This paper uses genetic approaches in a mouse model to remove function of the Brachyury (T) transcription factor from notochord precursor cells, which show that T regulates notochord cell fate and is consequently essential for normal spine formation. However, progenitor cells deprived of T survive and adopt neural and mesenchymal fates. They proliferate at a high rate and can adopt a mesenchymal morphology, features associated with aggressive behavior in tumors. These results raise concern about appropriate rationales to therapeutically target T in chordomas, sarcomas that arise from notochord rests, as well as other cancers expressing T. The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial–mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers.
