Pézeron Guillaume, Millen Kat, Boukhatmi Hadi, Bray Sarah
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
J Cell Sci. 2014 Nov 1;127(Pt 21):4634-44. doi: 10.1242/jcs.151787. Epub 2014 Sep 12.
There is growing evidence that activation of the Notch pathway can result in consequences on cell morphogenesis and behaviour, both during embryonic development and cancer progression. In general, Notch is proposed to coordinate these processes by regulating expression of key transcription factors. However, many Notch-regulated genes identified in genome-wide studies are involved in fundamental aspects of cell behaviour, suggesting a more direct influence on cellular properties. By testing the functions of 25 such genes we confirmed that 12 are required in developing adult muscles, consistent with roles downstream of Notch. Focusing on three, Reck, rhea/talin and trio, we verify their expression in adult muscle progenitors and identify Notch-regulated enhancers in each. Full activity of these enhancers requires functional binding sites for Su(H), the DNA-binding transcription factor in the Notch pathway, validating their direct regulation. Thus, besides its well-known roles in regulating the expression of cell-fate-determining transcription factors, Notch signalling also has the potential to directly affect cell morphology and behaviour by modulating expression of genes such as Reck, rhea/talin and trio. This sheds new light on the functional outputs of Notch activation in morphogenetic processes.
越来越多的证据表明,Notch信号通路的激活在胚胎发育和癌症进展过程中,均可对细胞形态发生和行为产生影响。一般认为,Notch通过调节关键转录因子的表达来协调这些过程。然而,在全基因组研究中鉴定出的许多Notch调节基因都参与了细胞行为的基本方面,这表明Notch对细胞特性有更直接的影响。通过测试25个此类基因的功能,我们证实其中12个基因在成年肌肉发育中是必需的,这与Notch下游的作用一致。聚焦于Reck、rhea/踝蛋白和trio这三个基因,我们验证了它们在成年肌肉祖细胞中的表达,并在每个基因中鉴定出Notch调节的增强子。这些增强子的完全活性需要Notch信号通路中的DNA结合转录因子Su(H)的功能性结合位点,从而验证了它们的直接调控作用。因此,除了在调节细胞命运决定转录因子表达方面的众所周知的作用外,Notch信号传导还具有通过调节Reck、rhea/踝蛋白和trio等基因的表达来直接影响细胞形态和行为的潜力。这为Notch激活在形态发生过程中的功能输出提供了新的线索。