Stevens Brian, Popp Riley, Valera Heather, Krueger Kyle, Petersen Christian P
Department of Molecular Biosciences, Northwestern University; Evanston IL 60208.
Robert Lurie Comprehensive Cancer Center, Northwestern University; Evanston IL 60208.
bioRxiv. 2024 Dec 23:2024.12.23.630141. doi: 10.1101/2024.12.23.630141.
The activation of progenitor cells near wound sites is a common feature of regeneration across species, but the conserved signaling mechanisms responsible for this step in whole-body regeneration are still incompletely understood. The acoel undergoes whole-body regeneration using Piwi+ pluripotent adult stem cells (neoblasts) that accumulate at amputation sites early in the regeneration process. The EGFR signaling pathway has broad roles in controlling proliferation, migration, differentiation, and cell survival across metazoans. Using a candidate RNAi screening approach, we identify the EGFR and Neuregulin genes as essential for blastema formation. Structure prediction of NRG-1 and ERBB4-2 proteins supports the likelihood of these factors interacting directly. After amputation injuries, expression is induced in body-wall muscle cells at the wound site by 6 hours and localizes to the tip of the outgrowing blastema over the next several days, while is broadly expressed, including in muscle and neoblasts. Under and conditions that impair blastema formation, animals still undergo the earliest responses to injury to activate expression of the Early Growth Response transcription factor , indicating a crucial role for EGFR signaling downstream of initial wound activation. and animals possess Piwi+ and H3P+ mitotic neoblasts which hyperproliferate normally after amputation, but these cells fail to accumulate at the wound site. Therefore, muscle provides a source for Neuregulin-ErbB signaling necessary for the mobilization of proliferative progenitors to enable blastema outgrowth for whole-body regeneration in . These results indicate a shared functional requirement for muscle signaling to enable regeneration between planarians and acoels across 550 million years of evolution.
伤口部位附近祖细胞的激活是跨物种再生的一个共同特征，但负责全身再生这一步骤的保守信号机制仍未完全了解。无肠目动物利用Piwi+多能成体干细胞（新细胞）进行全身再生，这些干细胞在再生过程早期聚集在截肢部位。表皮生长因子受体（EGFR）信号通路在控制后生动物的增殖、迁移、分化和细胞存活方面具有广泛作用。通过候选RNA干扰筛选方法，我们确定EGFR和神经调节蛋白基因对芽基形成至关重要。NRG-1和ERBB4-2蛋白的结构预测支持了这些因子直接相互作用的可能性。截肢损伤后，伤口部位的体壁肌肉细胞在6小时内诱导表达，并在接下来的几天内定位于生长中的芽基尖端，而[此处原文缺失相关基因名称]广泛表达，包括在肌肉和新细胞中。在损害芽基形成的[此处原文缺失相关条件名称]和[此处原文缺失相关条件名称]条件下，动物仍会对损伤做出最早反应，以激活早期生长反应转录因子[此处原文缺失相关基因名称]的表达，这表明EGFR信号在初始伤口激活下游起关键作用。[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]动物拥有Piwi+和H3P+有丝分裂新细胞，这些细胞在截肢后通常会过度增殖，但这些细胞无法在伤口部位积累。因此，肌肉为神经调节蛋白-表皮生长因子受体（Neuregulin-ErbB）信号提供了来源，这是动员增殖祖细胞以使芽基生长从而实现无肠目动物全身再生所必需的。这些结果表明，在5.5亿年的进化过程中，肌肉信号对于涡虫和无肠目动物之间实现再生具有共同的功能需求。
