egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians
egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians
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DOI：
10.1242/dev.101345
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发表时间：
2014-05-01
期刊：
影响因子：
4.6
通讯作者：
Cebria, Francesc
中科院分区：
文献类型：
--
作者：
Fraguas, Susanna;Barberan, Sara;Cebria, Francesc
在淡水真涡虫的再生过程中，极性和图案程序在决定头部或尾部在前部或后部伤口处再生方面起着至关重要的作用。这个决定是在截肢后不久做出的。Wnt/β-连环蛋白和Hh信号通路在重建前后（AP）极性中的关键作用已得到充分证实。然而，根据其AP身份控制芽基的生长和分化的机制还不太清楚。先前的研究已经描述了Smed-egfr-3（一种涡虫表皮生长因子受体）在芽基生长和分化中的作用。在这里，我们确定Smed-EGFR-4，属于早期生长反应基因家族的锌指转录因子，作为Smed-EGFR-3的假定下游靶点。Smed-STAT-4主要在中枢神经系统中表达，其沉默抑制前部再生而不影响后部区域的再生。针对Wnt/β-catenin通路不同元件的单一和组合RNA干扰，以及脑特异性标记物和前部特异性标记物的表达分析，揭示了Smed-EGFR-4：（1）在两个阶段表达：早期Smed-EGFR-3非依赖性阶段和晚期Smed-EGFR-3依赖性阶段;（2）在再生的早期阶段是脑原基分化所必需的;和（3）它似乎拮抗Wnt/β-连环蛋白途径的活性以允许头部再生。这些结果表明，一个保守的EGFR/EGFR通路在细胞分化过程中起着重要的作用，在涡虫再生，并表明早期脑分化和头部再生的适当进展之间的关联。
During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/beta-catenin and Hh signaling pathways in re-establishing anterior-posterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/beta-catenin pathway, together with expression analysis of brain-and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phases an early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/beta-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.