Notch activation of Jagged1 contributes to the assembly of the arterial wall.
Notch activation of Jagged1 contributes to the assembly of the arterial wall.
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DOI：
10.1161/circulationaha.111.047159
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发表时间：
2012-01-17
期刊：
影响因子：
37.8
通讯作者：
Epstein JA
中科院分区：
文献类型：
--
作者：
Manderfield LJ;High FA;Engleka KA;Liu F;Li L;Rentschler S;Epstein JA
血管平滑肌前体中的Notch信号传导是平滑肌分化所必需的。内皮上的Jagged 1表达激活血管平滑肌前体（包括神经嵴起源的血管平滑肌前体）中的Notch，以启动成熟血管中平滑肌层的形成。在这里，我们表明，锯齿状蛋白1是一个直接的Notch目标在平滑肌，导致一个正反馈回路和横向诱导，传播一个波的平滑肌分化在主动脉弓动脉的发展。在体内，我们表明，Notch抑制心脏神经嵴损伤锯齿蛋白1 mRNA的表达，并导致平滑肌分化不足，导致主动脉弓动脉缺损。离体，Jagged 1配体激活神经嵴外植体中的Notch，并导致Jagged 1 mRNA的激活，这是一种被Notch抑制阻断的反应。我们研究了15个进化保守区域内的锯齿状蛋白1基因组位点，并确定了一个单一的Notch反应元件内的第二个内含子。该元件包含一个功能性Rbp-J结合位点，通过荧光素酶报告和染色质免疫沉淀试验证明，足以概括转基因小鼠中Jagged 1在主动脉弓动脉的表达。神经嵴中Jagged 1的缺失损害血管平滑肌分化并导致主动脉弓动脉缺损。总之，这些结果提供了一种侧向诱导机制，允许在新生动脉内皮管周围形成多层平滑肌壁，并将Jagged 1鉴定为直接Notch靶点。
Notch signaling in vascular smooth muscle precursors is required for smooth muscle differentiation. Jagged1 expression on endothelium activates Notch in vascular smooth muscle precursors including those of neural crest origin to initiate the formation of a smooth muscle layer in a maturing blood vessel. Here, we show that Jagged1 is a direct Notch target in smooth muscle, resulting in a positive feedback loop and lateral induction that propagates a wave of smooth muscle differentiation during aortic arch artery development. In vivo, we show that Notch inhibition in cardiac neural crest impairs Jagged1 mRNA expression and results in deficient smooth muscle differentiation and resultant aortic arch artery defects. Ex vivo, Jagged1 ligand activates Notch in neural crest explants and results in activation of Jagged1 mRNA, a response that is blocked by Notch inhibition. We examine 15 evolutionary conserved regions within the Jagged1 genomic locus and identify a single Notch response element within the second intron. This element contains a functional Rbp-J binding site demonstrated by luciferase reporter and chromatin immunoprecipitation assays and is sufficient to recapitulate aortic arch artery expression of Jagged1 in transgenic mice. Loss of Jagged1 in neural crest impairs vascular smooth muscle differentiation and results in aortic arch artery defects. Taken together, these results provide a mechanism for lateral induction that allows for a multilayered smooth muscle wall to form around a nascent arterial endothelial tube and identify Jagged1 as a direct Notch target.