Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration
Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration
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DOI：
10.1242/dev.133363
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发表时间：
2016-08-01
期刊：
影响因子：
4.6
通讯作者：
Monaghan, James R.
中科院分区：
文献类型：
--
作者：
Farkas, Johanna E.;Freitas, Polina D.;Monaghan, James R.
墨西哥蝾螈（Ambystoma mexicanum）能够完全再生截肢，但肢体的去神经支配会抑制受伤后增殖性肿块（称为芽基）的形成。这种现象背后的分子基础仍然知之甚少，但之前的研究表明，神经通过分泌必需的生长促进因子来支持再生。必须在芽基中找到一种重要的神经源性因子，能够挽救失神经肢体的再生，并且抑制它必须阻止再生。在这里，我们证明了蝾螈中的神经分泌蛋白 Neuregulin-1 (NRG1) 满足所有这些标准。 NRG1 及其活性受体 ErbB2 的免疫组织化学和原位杂交表明，它们在再生胚基中表达，但在去神经支配后丢失。 NRG1 在胚基形成之前定位于伤口上皮，随后在增殖的胚基细胞中强烈表达。通过植入 NRG1 浸泡的珠子来补充，可挽救去神经支配肢体的手指再生，而对 NRG1 信号传导的药理抑制可减少细胞增殖，阻止胚基形成并诱导完全神经支配的肢体中的异常胶原蛋白沉积。总而言之，我们的结果表明，神经依赖性 NRG1/ErbB2 信号传导促进再生肢体中的胚基增殖，并可能在胚基形成中发挥重要作用，从而深入了解为什么蝾螈肢体再生需要神经这一长期存在的问题。
The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration.