奥地利科学院分子生物技术研究所E. M. Tanaka小组的一项最新研究提出了肢体再生中位置记忆的分子基础。2025年5月21日出版的《自然》发表了这项成果。

研究小组确定了一个正反馈回路，这是负责后身份的蝾螈肢体（Ambystoma mexicanum）。后肢细胞在发育过程中表达残留的Hand2转录因子，这使它们在截肢后形成Shh信号中心。在再生过程中，Shh信号也在Hand2表达的上游。再生后，Shh被关闭，但Hand2被保留，以保护后向记忆。小组将这个再生回路的主题转换为前细胞到后细胞的记忆状态。在再生过程中，前部细胞短暂暴露于Shh，启动了一个异位的Hand2 - Shh循环，导致稳定的Hand2表达和持久的Shh表达能力。他们的研究结果暗示了位置记忆稳定性中的正反馈，并揭示了位置记忆在一个方向上（从前到后）比在另一个方向上更容易被重新编程。改变再生细胞的位置记忆会改变其信号输出，这对组织工程具有重要意义。

据了解，蝾螈肢体的截肢会触发前肢和后肢结缔组织细胞形成不同的信号中心，共同促进再生。前面和后面的身份是在发育过程中建立起来的，并且被认为以位置记忆的形式持续一生。然而，位置记忆的分子基础和位置记忆是否可以改变仍然是未知的。

附：英文原文

Title: Molecular basis of positional memory in limb regeneration

Author: Otsuki, L., Plattner, S. A., Taniguchi-Sugiura, Y., Falcon, F., Tanaka, E. M.

Issue&Volume: 2025-05-21

Abstract: The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration1. Anterior and posterior identities are established during development and are thought to persist for the whole life in the form of positional memory2. However, the molecular basis of positional memory and whether positional memory can be altered remain unknown. Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory. We used this regeneration circuitry to convert anterior cells to a posterior-cell memory state. Transient exposure of anterior cells to Shh during regeneration kick-started an ectopic Hand2–Shh loop, leading to stable Hand2 expression and lasting competence to express Shh. Our results implicate positive-feedback in the stability of positional memory and reveal that positional memory is reprogrammed more easily in one direction (anterior to posterior) than in the other. Modifying positional memory in regenerative cells changes their signalling outputs, which has implications for tissue engineering.

DOI: 10.1038/s41586-025-09036-5

Source: https://www.nature.com/articles/s41586-025-09036-5