Epidermal growth factor-dependent enhancement of axonal regeneration in the pond snail Lymnaea stagnalis: Role of phagocyte survival

Peripheral nerve injury triggers complex responses from neuronal as well as from multiple nonneuronal cell types. These responses are coordinated by a wide spectrum of secreted and nonsecreted factors, including growth factors, cytokines, and cell adhesion molecules. These molecules originate from different sources and act both locally at the site of injury as well as centrally at the location of the neuronal cell bodies. One of the signal systems frequently implicated in this process is the epidermal growth factor (EGF) family and its receptors. Expression of members of this family as well as that of EGF-receptors is upregulated in different cell types after peripheral nerve injury. However, the functional significance of this response is unclear. Using a simple invertebrate model system (Lymnaea stagnalis), the present study implicates the EGF/EGF-receptor system in the survival of ionized calcium-binding adaptor molecule 1 (Iba1)-positive phagocytes that reside in the nervous system. We show that inhibiting the EGF-signaling pathway enhances cell death in this type of cell, an effect paralleled by a substantial reduction in axonal regeneration. Therefore, complementing our previous observation that Lymnaea EGF provides trophic support to axotomized neurons, the present results emphasize the significance of nonneuronal actions of EGF receptor ligands in axonal regeneration. Thus, we add a novel perspective to the ongoing discussion on the functional significance of the EGF signaling system in the injury responses of the nervous system.