Intracellular control of developmental and regenerative axon growth

Abstract

Axon growth is a highly regulated process that requires stimulating signals from extracellular factors. The extracellular signals are then transduced to regulate coordinately gene expression and local axon assembly. Growth factors, especially neurotrophins that act via receptor tyrosine kinases, have been heavily studied as extracellular factors that stimulate axon growth. Downstream of receptor tyrosine kinases, recent studies have suggested that phosphatidylinositol-3 kinase (PI3K) regulates local assembly of axonal cytoskeleton, especially microtubules, via glycogen synthase kinase 3b (GSK-3b) and multiple microtubule binding proteins. The role of extracellular signal regulated kinase (ERK) signalling in regulation of local axon assembly is less clear, but may involve the regulation of local protein translation. Gene expression during axon growth is regulated by transcription factors, among which cyclic AMP response element binding protein and nuclear factors of activated T-cells (NFATs) are known to be required for neurotrophin (NT)-induced axon extension. In addition to growth factors, extracellular matrix molecules and neuronal activity contribute importantly to control axon growth. Increasingly, evidence suggests that these influences act to enhance growth via coordinating with growth factor signalling. Finally, evidence is emerging that developmental versus regenerative axon growth may be mediated by distinct signalling pathways, both at the level of gene transcription and at the level of local axon assembly.

Sustained GSK3 activity markedly facilitates nerve regeneration

“…In the developing nervous system, GSK3 regulates the activity of several microtubule associated proteins (MAPs) 4,13,[21][22][23]38,39 and thereby controls directed growth cone advancement and guidance. One of these proteins is MAP1B, which is required for axon growth 40 .…”

Initiating and Growing an Axon

“…GSK-3 has multiple substrates that have the potential to regulate tubulin polymerization and microtubule stability. These include the microtubule plus-end binding proteins APC and CLASP2, CRMP-2, which is localized to axon tips and may play a role in cargo delivery and tubulin polymerization, and the microtubule associated proteins MAP1B and tau (reviewed in Zhou and Snider 2006). Details of how these proteins function and how they are regulated by GSK-3 phosphorylation remain obscure.…”

“…Thus, many studies with the major pharmacological inhibitors PD98059 and U0126 show striking inhibition of axon growth induced by neurotrophins and other factors acting via receptor tyrosine kinases (see Zhou and Snider 2006, for a review). Further, both loss and gain of function studies in vitro suggested strong axon growth promoting functions for Ras, Raf, and ERK/MAPK (Markus et al 2002).…”

An in vitro spinal cord injury model to screen neuroregenerative materials

“…the brain and spinal cord) is a particularly challenging tissue system in this regard, due to the complex cellular dynamics and intricate (cardinal) pathophysiological events displayed after neurological injury [13]. For example, following SCI in vivo: astrocytes upregulate expression of the astrocyte-specific marker glial fibrillary acidic protein (GFAP), within and adjacent to lesions, to form a scar that constitutes a critical barrier to axonal regeneration [14]; microglia (the immune-competent cells of the CNS) infiltrate into lesion sites and are responsible for the breakdown and phagocytosis of cellular debris and toxic substances following injury [15,16]; and limited, spontaneous sprouting of nerve fibers occurs from lesion margins, with the extent of regeneration declining with age [17].…”