Transcriptional regulators in the Hippo signaling pathway control organ growth in Xenopus tadpole tail regeneration
Transcriptional regulators in the Hippo signaling pathway control organ growth in Xenopus tadpole tail regeneration
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DOI：
10.1016/j.ydbio.2014.09.018
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发表时间：
2014-12-01
影响因子：
2.7
通讯作者：
Yokoyama, Hitoshi
中科院分区：
文献类型：
--
作者：
Hayashi, Shinichi;Ochi, Haruki;Yokoyama, Hitoshi
组织的大小和形状受到细胞和组织之间同步过程的严格控制，以产生完整的器官。Hippo信号通路通过抑制性激酶级联调节双重信号转导状态来控制细胞增殖和凋亡。Yap 1和Tead是Hippo信号激酶级联反应下游的转录调节因子，在调节细胞增殖中起重要作用。在两栖动物的肢体或尾部再生中，当达到正确的大小时，局部组织的生长终止，这表明在表型器官水平的再生过程中，器官的大小受到严格控制。我们最近证明了Yap 1是非洲爪蟾蝌蚪肢芽再生所必需的（Hayashi等人，2014年，Dev. 388，57-67），但脊椎动物表型再生中Hippo途径与器官大小控制之间的分子联系尚未完全理解。为了研究河马途径转录调节因子在表型再生中的需求，包括器官大小控制，我们通过在转基因动物系中的热休克启动子下过表达显性阴性形式的雅普（dn雅普）或Tead 4（dnTead 4）来抑制这些调节因子在非洲爪蟾蝌蚪尾再生过程中。每一种抑制都导致再生缺陷，伴随着细胞有丝分裂减少和细胞凋亡增加。单细胞基因操作实验表明，Tead 4细胞自主调节再生尾中神经祖细胞的存活。在两栖动物中，在近端水平的尾巴（深截肢）比远端水平（浅截肢）更快地再生，以在相似的时间恢复原始大小的尾巴。然而，dnTead 4过表达废除了尾部再生的位置依赖性差异生长率。这些结果表明，在河马途径，Tead 4和Yap 1，转录调节所需的一般脊椎动物表型再生以及在附件再生的器官大小控制。在再生医学中，这些发现应该有助于为患者的身体开发具有正确尺寸的三维器官。(C)2014爱思唯尔公司All rights reserved.
The size and shape of tissues are tightly controlled by synchronized processes among cells and tissues to produce an integrated organ. The Hippo signaling pathway controls both cell proliferation and apoptosis by dual signal-transduction states regulated through a repressive kinase cascade. Yap1 and Tead, transcriptional regulators that act downstream of the Hippo signaling kinase cascade, have essential roles in regulating cell proliferation. In amphibian limb or tail regeneration, the local tissue outgrowth terminates when the correct size is reached, suggesting that organ size is strictly controlled during epimorphic organ-level regeneration. We recently demonstrated that Yap1 is required for the regeneration of Xenopus tadpole limb buds (Hayashi et al., 2014, Dev. Biol. 388, 57-67), but the molecular link between the Hippo pathway and organ size control in vertebrate epimorphic regeneration is not fully understood. To examine the requirement of Hippo pathway transcriptional regulators in epimorphic regeneration, including organ size control, we inhibited these regulators during Xenopus tadpole tail regeneration by overexpressing a dominant-negative form of Yap (dnYap) or Tead4 (dnTead4) under a heat-shock promoter in transgenic animal lines. Each inhibition resulted in regeneration defects accompanied by reduced cell mitosis and increased apoptosis. Single-cell gene manipulation experiments indicated that Tead4 cell-autonomously regulates the survival of neural progenitor cells in the regenerating tail. In amphibians, amputation at the proximal level of the tail (deep amputation) results in faster regeneration than that at the distal level (shallow amputation), to restore the original-sized tail with similar timing. However, dnTead4 overexpression abolished the position-dependent differential growth rate of tail regeneration. These results suggest that the transcriptional regulators in the Hippo pathway, Tead4 and Yap1, are required for general vertebrate epimorphic regeneration as well as for organ size control in appendage regeneration. In regenerative medicine, these findings should contribute to the development of three-dimensional organs with the correct size for a patient's body. (C) 2014 Elsevier Inc. All rights reserved.