Haploinsufficiency of Def activates p53-dependent TGFβ signalling and causes scar formation after partial hepatectomy.
Haploinsufficiency of Def activates p53-dependent TGFβ signalling and causes scar formation after partial hepatectomy.
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Def 的单倍体不足激活 p53 依赖性 TGF beta 信号传导并导致部分肝切除术后疤痕形成
DOI：
10.1371/journal.pone.0096576
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Peng J
中科院分区：
文献类型：
--
作者：
Zhu Z;Chen J;Xiong JW;Peng J
后生动物的肝脏表现出显着的能力，再生失去的肝脏质量，而不会留下疤痕后，部分肝切除术（PH）。虽然以前的研究已经确定了几种不同的信号通路的组成部分，这些信号通路对肝再生过程中肝细胞增殖的激活至关重要，但使这种再生发生而不伴随瘢痕形成的机制仍然知之甚少。在这里，我们使用成年斑马鱼肝脏，它可以在PH后两周内再生，作为一个新的遗传模型来解决这个重要的问题。我们专注于消化器官扩张因子（Def），核仁蛋白，最近已被证明与钙蛋白酶3（Capn 3）的复合物，介导p53降解特异性在核仁中，在肝再生的作用。首先，我们发现Def表达在截肢后的野生型肝脏中上调，并且defhi 429/+杂合突变体（def+/−）在肝脏中患有Def单倍不足。然后，我们发现促炎细胞因子的表达在def+/−肝脏中上调，这导致PH后白细胞迁移和清除的扭曲。由于长期的炎症反应，转化生长因子β（TGFβ）信号传导在def+/−伤口表皮中被激活，这导致截肢部位的纤维化。def+/-中的纤维化瘢痕形成通过Def的过度表达、p53的功能丧失以及抗炎药物地塞米松或TGFβ信号传导抑制剂SB 431542的治疗而被阻断。我们最后表明，Def-p53途径抑制纤维化瘢痕形成，至少部分，通过调节促炎因子，高迁移率族蛋白1的表达。我们的结论是，新的Def- p53核仁途径的功能，特别是防止疤痕形成在截肢部位在正常截肢的肝脏。
The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a scar following partial hepatectomy (PH). Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (Def), a nucleolar protein which has recently been shown to complex with calpain3 (Capn3) to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that Def expression is up-regulated in the wild-type liver following amputation, and that the defhi429/+ heteroozygous mutant (def+/−) suffers from haploinsufficiency of Def in the liver. We then show that the expression of pro-inflammatory cytokines is up-regulated in the def+/− liver, which leads to distortion of the migration and the clearance of leukocytes after PH. Transforming growth factor β (TGFβ) signalling is thus activated in the wound epidermis in def+/− due to a prolonged inflammatory response, which leads to fibrosis at the amputation site. Fibrotic scar formation in def+/− is blocked by the over-expression of Def, by the loss-of-function of p53, and by treatment with anti-inflammation drug dexamethasone or TGFβ-signalling inhibitor SB431542. We finally show that the Def- p53 pathway suppresses fibrotic scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel Def- p53 nucleolar pathway functions specifically to prevent a scar formation at the amputation site in a normal amputated liver.
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