title: Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT.
abstract: 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.
authors.affiliation: Cancer & Developmental Biology Laboratory (CDBL), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702;
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: School of Life Sciences, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.affiliation: Cancer & Developmental Biology Laboratory (CDBL), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702; mackems@mail.nih.gov.
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D047108:Embryonic Development; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D009672:Notochord / Q000196:embryology* / Q000378:metabolism; D054240:Primitive Streak / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D013234:Stem Cells / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein
keywords: Brachyury; EMT; cell fate; notochord