Notch signaling is required for lateral induction of Jagged1 during FGF-induced lens fiber differentiation.
Notch signaling is required for lateral induction of Jagged1 during FGF-induced lens fiber differentiation.
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DOI：
10.1016/j.ydbio.2009.05.566
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发表时间：
2009-08-01
影响因子：
2.7
通讯作者：
Zelenka, Peggy S.
中科院分区：
文献类型：
--
作者：
Saravanamuthu, Senthil S.;Gao, Chun Y.;Zelenka, Peggy S.
关键词：
先前对晶状体发育的研究表明，Notch信号通过维持晶状体前上皮的增殖前体池来调节晶状体纤维细胞的分化。然而，在纤维细胞分化开始后是否还需要Notch信号尚不清楚。本研究研究了Notch2和Jagged1 （Jag1）在体外FGF-2依赖性分化大鼠晶状体上皮组织中继发性纤维细胞分化中的作用。FGF在12-24小时内诱导Jag1表达和Notch2信号传导（通过激活的Notch2胞内结构域（N2ICD）的出现来判断）。这些变化与Notch效应因子Hes5的诱导、N-cadherin （N-cad）的上调和E-cadherin （E-cad）的下调有关，E-cadherin是纤维细胞分化的钙粘蛋白开关特征。Jag1的诱导被MAPK/ERK信号的特异性抑制剂U0126有效阻断，表明需要通过FGF受体下游的这一途径进行信号传导。其他激活MAPK/ERK信号的生长因子（EGF、PDGF、IGF）不诱导Jag1。使用γ分泌酶抑制剂DAPT和L-685、458或抗Jag1抗体抑制Notch信号，可显著降低fgf依赖性的Jag1表达，显示Notch依赖性的侧诱导。此外，Notch信号的抑制降低了N-cad和细胞周期蛋白依赖性激酶抑制剂p57Kip2的表达，表明Notch信号在次生纤维细胞分化中起直接作用。这些结果表明，缺口介导的Jag1横向诱导是fgf依赖性晶状体纤维细胞分化的重要组成部分。
Previous studies of the developing lens have shown that Notch signaling regulates differentiation of lens fiber cells by maintaining a proliferating precursor pool in the anterior epithelium. However, whether Notch signaling is further required after the onset of fiber cell differentiation is not clear. This work investigates the role of Notch2 and Jagged1 (Jag1) in secondary fiber cell differentiation using rat lens epithelial explants undergoing FGF-2 dependent differentiation in vitro. FGF induced Jag1 expression and Notch2 signaling (as judged by the appearance of activated Notch2 Intracellular Domain (N2ICD)) within 12–24 hours. These changes were correlated with induction of the Notch effector, Hes5, upregulation of N-cadherin (N-cad), and downregulation of E-cadherin (E-cad), a cadherin switch characteristic of fiber cell differentiation. Induction of Jag1 was efficiently blocked by U0126, a specific inhibitor of MAPK/ERK signaling, indicating a requirement for signaling through this pathway downstream of the FGF receptor. Other growth factors that activate MAPK/ERK signaling (EGF, PDGF, IGF) did not induce Jag1. Inhibition of Notch signaling using gamma secretase inhibitors DAPT and L-685, 458 or anti-Jag1 antibody markedly decreased FGF-dependent expression of Jag1 demonstrating Notch-dependent lateral induction. In addition, inhibition of Notch signaling reduced expression of N-cad, and the cyclin dependent kinase inhibitor, p57Kip2, indicating a direct role for Notch signaling in secondary fiber cell differentiation. These results demonstrate that Notch-mediated lateral induction of Jag1 is an essential component of FGF-dependent lens fiber cell differentiation.
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作者：
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作者：
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DOI：
10.1084/jem.20071082
发表时间：
2007-11-26
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Leong KG;Niessen K;Kulic I;Raouf A;Eaves C;Pollet I;Karsan A
通讯作者：
Karsan A