Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
Institute Biology Leiden, Leiden University, Leiden, the Netherlands.
Mol Cell Biol. 2018 Jan 29;38(4). doi: 10.1128/MCB.00515-17. Print 2018 Feb 15.
Regeneration of the zebrafish caudal fin following amputation occurs through wound healing, followed by formation of a blastema, which produces cells to replace the lost tissue in the final phase of regenerative outgrowth. We show that zebrafish embryos, lacking functional Shp2, fail to regenerate their caudal fin folds. Rescue experiments indicated that Shp2a has a functional signaling role, requiring its catalytic activity and SH2 domains but not the two C-terminal tyrosine phosphorylation sites. Surprisingly, expression of Shp2a variants with increased and reduced catalytic activity, respectively, rescued caudal fin fold regeneration to similar extents. Expression of and , indicative of formation of the wound epidermis and distal blastema, respectively, suggested that these processes occurred in zebrafish embryos. However, cell proliferation and MAPK phosphorylation were reduced. Pharmacological inhibition of MEK1 in wild-type zebrafish embryos phenocopied loss of Shp2. Our results suggest an essential role for Shp2a-mitogen-activated protein kinase (MAPK) signaling in promoting cell proliferation during zebrafish embryo caudal fin fold regeneration.
斑马鱼尾部在截肢后会通过伤口愈合，然后形成一个胚基，在再生性生长的最后阶段，胚基产生细胞来替代丢失的组织，从而实现再生。我们发现，缺乏功能性 Shp2 的斑马鱼胚胎无法再生其尾部褶皱。挽救实验表明，Shp2a 具有功能性信号转导作用，需要其催化活性和 SH2 结构域，但不需要两个 C 末端酪氨酸磷酸化位点。令人惊讶的是，表达具有增强和降低催化活性的 Shp2a 变体分别在相似程度上挽救了尾部褶皱的再生。 和 的表达分别提示了伤口表皮和远端胚基的形成，这表明这些过程发生在 Shp2 缺失的斑马鱼胚胎中。然而，细胞增殖和 MAPK 磷酸化减少。在野生型斑马鱼胚胎中，MEK1 的药理学抑制作用模拟了 Shp2 的缺失。我们的结果表明，Shp2a-丝裂原活化蛋白激酶（MAPK）信号在促进斑马鱼胚胎尾部褶皱再生过程中的细胞增殖中起着重要作用。
