Rich Ashley, Lu Ziqi, Simone Alessandro De, Garcia Lucas, Janssen Jacqueline, Ando Kazunori, Ou Jianhong, Vergassola Massimo, Poss Kenneth D, Talia Stefano Di
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Duke Center for Quantitative Living Systems, Duke University Medical Center, Durham, NC, USA.
bioRxiv. 2025 Jan 23:2025.01.23.634576. doi: 10.1101/2025.01.23.634576.
Regeneration of an amputated salamander limb or fish fin restores pre-injury size and structure, illustrating the phenomenon of positional memory. Although appreciated for centuries, the identity of position-dependent cues and how they control tissue growth are not resolved. Here, we quantify Erk signaling events in whole populations of osteoblasts during zebrafish fin regeneration. We find that osteoblast Erk activity is dependent on Fgf receptor signaling and organized into millimeter-long gradients that extend from the distal tip to the amputation site. Erk activity scales with the amount of tissue amputated, predicts the likelihood of osteoblast cycling, and predicts the size of regenerated skeletal structures. Mathematical modeling suggests gradients are established by the transient deposition of long-lived ligands that are transported by tissue growth. This concept is supported by the observed scaling of expression of the essential epidermal ligand with extents of amputation. Our work provides evidence that localized, scaled expression of pro-regenerative ligands instructs long-range signaling and cycling to control skeletal size in regenerating appendages.
蝾螈肢体或鱼鳍被截断后再生，可恢复损伤前的大小和结构，这说明了位置记忆现象。尽管这一现象已被认识数百年，但位置依赖性信号的特性以及它们如何控制组织生长仍未得到解决。在这里，我们在斑马鱼鳍再生过程中对成骨细胞的整个群体中的Erk信号事件进行了量化。我们发现成骨细胞的Erk活性依赖于Fgf受体信号传导，并组织成从远端尖端延伸到截断部位的毫米级长梯度。Erk活性与截断的组织量成比例，预测成骨细胞循环的可能性，并预测再生骨骼结构的大小。数学模型表明，梯度是由组织生长运输的长寿配体的瞬时沉积建立的。这一概念得到了观察到的必需表皮配体表达与截断程度的比例关系的支持。我们的工作提供了证据，即促再生配体的局部、成比例表达指导远程信号传导和循环，以控制再生附肢中的骨骼大小。
