Notch signaling coordinates cellular proliferation with differentiation during zebrafish fin regeneration
Notch signaling coordinates cellular proliferation with differentiation during zebrafish fin regeneration
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DOI：
10.1242/dev.087452
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发表时间：
2013-04-01
期刊：
影响因子：
4.6
通讯作者：
Weidinger, Gilbert
中科院分区：
文献类型：
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作者：
Grotek, Bartholomaeus;Wehner, Daniel;Weidinger, Gilbert
斑马鱼可以通过形成囊胚（一种由未分化的前体细胞组成的增殖体）使被切除的鳍完全再生。在再生生长过程中，囊胚增殖必须与细胞分化紧密协调，但很少有人知道这是如何实现的。在这里，我们发现Notch信号对于维持胚母细胞处于增殖未分化状态至关重要。我们发现Notch通路被激活，以响应鳍切除的高度增殖的囊胚区域。化学干扰Notch信号导致再生完全受阻。Notch信号并不需要最早的已知细胞过程，即成骨细胞的去分化和迁移，但专门干扰囊胚细胞的增殖。有趣的是，通过Notch受体细胞内结构域（NICD）的错误表达而过度激活该通路同样会抑制再生产物。在过表达nicd的鳍中，胚细胞的整体增殖并未增强，而是扩展到通常发生细胞分化的近端区域。同样，在Notch持续激活后，胚质和表皮基因表达区侵入近端区域。同时，NICD的过表达抑制了成骨细胞的分化，导致未分化胚的扩大。综上所述，这些数据表明Notch信号活动维持胚细胞处于增殖状态，从而在再生生长过程中协调增殖和分化。
Zebrafish can completely regenerate amputated fins via formation of a blastema, a proliferative mass of undifferentiated precursor cells. During regenerative growth, blastema proliferation must be tightly coordinated with cellular differentiation, but little is known about how this is achieved. Here, we show that Notch signaling is essential for maintenance of blastema cells in a proliferative undifferentiated state. We found that the Notch pathway is activated in response to fin amputation in the highly proliferative region of the blastema. Chemical interference with Notch signaling resulted in a complete block of regeneration. Notch signaling was not required for the earliest known cellular processes during blastema formation, i.e. dedifferentiation and migration of osteoblasts, but specifically interfered with proliferation of blastema cells. Interestingly, overactivation of the pathway via misexpression of the intracellular domain of the Notch receptor (NICD) likewise inhibited regenerative outgrowth. In NICD-overexpressing fins, overall blastemal cell proliferation was not enhanced, but expanded into proximal regions where cellular differentiation normally occurs. Similarly, blastemal and epidermal gene expression territories invaded proximal regions upon sustained Notch activation. Concomitantly, NICD overexpression suppressed differentiation of osteoblasts and caused an expansion of the undifferentiated blastema. Together, these data suggest that Notch signaling activity maintains blastemal cells in a proliferative state and thus coordinates proliferation with differentiation during regenerative growth.