Notch regulates blastema proliferation and prevents differentiation during adult zebrafish fin regeneration
Notch regulates blastema proliferation and prevents differentiation during adult zebrafish fin regeneration
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DOI：
10.1242/dev.087346
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发表时间：
2013-04-01
期刊：
影响因子：
4.6
通讯作者：
Luis de la Pompa, Jose
中科院分区：
文献类型：
--
作者：
Muench, Juliane;Gonzalez-Rajal, Alvaro;Luis de la Pompa, Jose
斑马鱼有能力再生几个器官，包括心脏和鳍。鳍再生是表型的，涉及在截肢平面形成大量未分化的、增殖的间充质祖细胞样细胞，称为芽基。这种组织提供形成鳍的所有细胞类型，因此在损伤或截肢后，鳍的图案和结构完全恢复。芽基细胞如何保持这种祖细胞样状态还知之甚少。在这里，我们表明，Notch途径在鳍再生过程中起着至关重要的作用。Notch信号传导在芽基形成期间被激活，并且在整个再生过程中保持活性。Notch信号传导的化学抑制或吗啉代介导的敲低通过减少增殖伴随着芽基中Notch靶基因的表达减少而损害鳍再生。相反，Notch1受体（N1ICD）在再生鳍中的组成型活性形式的过表达导致增殖增加和芽基细胞标志物msxe和msxb的扩增，以及增殖调节因子aldh1a2的表达增加。这种芽基扩张阻止再生鳍的生长，如分化成骨细胞的减少和骨再生的抑制所示。我们的结论是，Notch信号保持芽基细胞在一个塑料，未分化和增殖状态，鳍再生的基本要求。
Zebrafish have the capacity to regenerate several organs, including the heart and fins. Fin regeneration is epimorphic, involving the formation at the amputation plane of a mass of undifferentiated, proliferating mesenchymal progenitor-like cells, called blastema. This tissue provides all the cell types that form the fin, so that after damage or amputation the fin pattern and structure are fully restored. How blastema cells remain in this progenitor-like state is poorly understood. Here, we show that the Notch pathway plays an essential role during fin regeneration. Notch signalling is activated during blastema formation and remains active throughout the regeneration process. Chemical inhibition or morpholino-mediated knockdown of Notch signalling impairs fin regeneration via decreased proliferation accompanied by reduced expression of Notch target genes in the blastema. Conversely, overexpression of a constitutively active form of the Notch1 receptor (N1ICD) in the regenerating fin leads to increased proliferation and to the expansion of the blastema cell markers msxe and msxb, as well as increased expression of the proliferation regulator aldh1a2. This blastema expansion prevents regenerative fin outgrowth, as indicated by the reduction in differentiating osteoblasts and the inhibition of bone regeneration. We conclude that Notch signalling maintains blastema cells in a plastic, undifferentiated and proliferative state, an essential requirement for fin regeneration.