A brief history of the study of nerve dependent regeneration

Abstract

Nerve dependence is a phenomenon observed across a stunning array of species and tissues. From zebrafish to fetal mice to humans, research across various animal models has shown that nerves are critical for the support of tissue repair and regeneration. Although the study of this phenomenon has persisted for centuries, largely through research conducted in salamanders, the cellular and molecular mechanisms of nerve dependence remain poorly-understood. Here we highlight the near-ubiquity and clinical relevance of vertebrate nerve dependence while providing a timeline of its study and an overview of recent advancements toward understanding the mechanisms behind this process. In presenting a brief history of the research of nerve dependence, we provide both historical and modern context to our recent work on nerve dependent limb regeneration in the Mexican axolotl.

Figure 1.

Timeline of landmark nerve dependency studies throughout history, along with a selection of the most recent findings in the field.

Figure 2.

(A) Diagram of the neurotrophic hypothesis, which states that nerve-secreted mitogens are transported from the dorsal root ganglia through the brachial plexus (BP) to support the proliferating blastema (BL). (B) Illustration of the inhibition hypothesis, in which denervation at the brachial plexus induces the release of inhibitory factors from Schwann Cells at the wound site. (C) Diagram of the accessory limb model, in which a peripheral nerve is deviated to a wound site to induce the formation of an accessory blastema (AB). (D) A control limb at 6 days post amputation (DPA). (E) A denervated limb at 6 DPA demonstrating extreme histolysis and inflammation. (F) The hyperinnervated regenerating blastema is highly proliferative at 14 DPA, as demonstrated by BrdU incorporation and staining. (G) Denervation eliminates beta-tubulin III staining of axons and substantially reduces the proliferative index of limbs at 14 DPA.