Mechanism of regeneration

Schematic summary of cellular and ultrastructural changes following axonal injury. 

Axotomy causes a detachment of neurite terminals and filling in of empty cell surfaces with CNS glia. 

Inside the neuron, there is a rearrangement of rough endoplasmitic reticulum cisternae or Nissl bodies (Raivich et.al.).

(Raivich G. et.al)– Summary of cellular mechanisms involved in successful regeneration: injury-induced signaling (A); cell body response involved in axonal growth (B); and molecular mechanisms of neurite outgrowth at the growth cone (C).

(A)   Axonal trauma induces a cessation of normal trophic retrograde transport (blue arrows), a rapid influx of cations resulting in an antidromal train of action potentials (red), and exposure to injury signals transported retrogradely via proteins containing nuclear localization signals (green), that may act in synergy to induce the biochemical activation in the neuronal cell body.

Ø     This regeneration programme includes enzymes regulating mRNA metabolism—ODC, TGT, intracellular cascades such as MAP kinases and PI3K-Akt, and complemented by enhanced nuclear localization and phosphorylation or other forms of activation (*)for a host of transcription factors (TF) including c-jun, etc., as well as numerous molecules that regulate cell death, including death domain carrying membrane proteins (p75, TNFR, fas) as well as cytoplasmic caspases and bcl-2 family members.

Ø     At the cut axon, the rapid influx of Ca2+ causes calpain activation and cytoskeletal remodeling that results in structured accumulation of anterogradely transported vesicles and cytoskeletal components, transforming the axon tip into an extension-competent growth cone.

(B) Regenerating neurons undergo transcription factor-dependent changes in mRNA and protein synthesis that result in the production and anterograde transport of vesicles and proteins (cell adhesion molecules, cytoskeleton, growth-associated proteins such as the GMC family members GAP43, CAP23 and MARCKS), that are needed for interacting with the local cell adhesion and guidance molecules (L1, NCAM, N-cadherin, laminin etc) and extending the axonal growth cone along the Schwann cells and the basal membrane substrate of the peripheral neural tubes.

(C) A brief overview of signals regulating neurite outgrowth at the axonal growth cone. This can involve a variety of interactions via preferentially homophilic (L1, NCAM) or heterophilic cell adhesion ligands (laminin, alpha7 beta1 integrin, ninjurin/gicerin), a variety of growth factors and their receptors such as FGF and FLTR3, and the phosphoinositol-4,5-diphosphates – PI(4,5)P2 – that associate with the GMC family of calcium/calmodulin ligands and Protein Kinase C (PKC) and regulate actin cytoskeleton polymerization, organization and disassembly. The anterograde axonal transport of vesicles, signaling molecules, cytoskeletal proteins and their mRNA plays a critical role in providing structural and regulatory components for axonal elongation.