Retinoic acid signaling controls the formation, proliferation and survival of the blastema during adult zebrafish fin regeneration
Retinoic acid signaling controls the formation, proliferation and survival of the blastema during adult zebrafish fin regeneration
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DOI：
10.1242/dev.065391
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发表时间：
2012-01-01
期刊：
影响因子：
4.6
通讯作者：
Begemann, Gerrit
中科院分区：
文献类型：
--
作者：
Blum, Nicola;Begemann, Gerrit
成年硬骨鱼通过一种称为表型再生的增殖依赖性过程重建被切断的鳍，在这个过程中，循环祖细胞的芽基取代了失去的鳍组织。控制从以前静止的残端组织形成芽基细胞和随后的芽基功能的遗传网络仍然知之甚少。在这里，我们研究了遗传干扰视黄酸（RA）信号形成的斑马鱼芽基的细胞和分子的后果。我们发现，RA信号上调后的第一个几个小时内断肢在残肢间充质，在那里它控制Fgf，Wnt/β-连环蛋白和Igf信号。在此阶段，RA途径的遗传抑制通过抑制残端细胞的细胞周期进入来阻断芽基形成，并损害基底表皮层（伤口表皮中的信号传导中心）的形成。在建立的胚基中，RA信号传导保持活跃，以通过控制抗凋亡因子bcl 2的表达来确保高度增殖的胚基群体的存活。此外，RA信号传导通过激活由Fgf和Wnt/β-连环蛋白信号传导介导的生长刺激信号以及通过减少通过生长抑制性非经典Wnt途径的信号传导来维持芽基增殖。RA在成年脊椎动物附肢再生中的内源性作用首次被发现。他们提供了一个机制框架，以了解以前的观察蝾螈，连接内源性来源的RA的再生过程本身，并支持的假设，RA信号通路是脊椎动物组织再生的重要组成部分。
Adult teleosts rebuild amputated fins through a proliferation-dependent process called epimorphic regeneration, in which a blastema of cycling progenitor cells replaces the lost fin tissue. The genetic networks that control formation of blastema cells from formerly quiescent stump tissue and subsequent blastema function are still poorly understood. Here, we investigated the cellular and molecular consequences of genetically interfering with retinoic acid (RA) signaling for the formation of the zebrafish blastema. We show that RA signaling is upregulated within the first few hours after fin amputation in the stump mesenchyme, where it controls Fgf, Wnt/beta-catenin and Igf signaling. Genetic inhibition of the RA pathway at this stage blocks blastema formation by inhibiting cell cycle entry of stump cells and impairs the formation of the basal epidermal layer, a signaling center in the wound epidermis. In the established blastema, RA signaling remains active to ensure the survival of the highly proliferative blastemal population by controlling expression of the anti-apoptotic factor bcl2. In addition, RA signaling maintains blastema proliferation through the activation of growth-stimulatory signals mediated by Fgf and Wnt/beta-catenin signaling, as well as by reducing signaling through the growth-inhibitory non-canonical Wnt pathway. The endogenous roles of RA in adult vertebrate appendage regeneration are uncovered here for the first time. They provide a mechanistic framework to understand previous observations in salamanders that link endogenous sources of RA to the regeneration process itself and support the hypothesis that the RA signaling pathway is an essential component of vertebrate tissue regeneration.