Coordinating Gene Expression and Axon Assembly to Control Axon Growth: Potential Role of GSK3 Signaling

Abstract

Axon growth requires the coordinated regulation of gene expression in the neuronal soma, local protein translation in the axon, anterograde transport of synthesized raw materials along the axon, and assembly of cytoskeleton and membranes in the nerve growth cone. Glycogen synthase kinase 3 (GSK3) signaling has recently been shown to play key roles in the regulation of axonal transport and cytoskeletal assembly during axon growth. GSK3 signaling is also known to regulate gene expression via controlling the functions of many transcription factors, suggesting that GSK3 may be an important regulator of gene transcription supporting axon growth. We review signaling pathways that control local axon assembly at the growth cone and gene expression in the soma during developmental or regenerative axon growth and discuss the potential involvement of GSK3 signaling in these processes, with a particular focus on how GSK3 signaling modulates the function of axon growth-associated transcription factors.

Keywords: axon growth; axon regeneration; glycogen synthase kinase 3; transcription factor.

Figure 1

Glycogen synthase kinase 3 controls axon growth by coordinating gene transcription and local microtubule dynamics in the growth cone. GSK3 phosphorylates a number of transcription factors and thereby controls their function and subsequent gene expression, which may play an important part in determining the intrinsic axon growth capacity. GSK3 is also known to phosphorylate several microtubule-binding proteins, which control distinct aspects of microtubule dynamics and assembly, and thereby controls local axon assembly at the axonal growth cone. The final outcome of axon regeneration is determined by the coordination between gene expression and local cytoskeletal assembly at the growth cone. Substrates whose activities are inhibited by GSK3 are depicted in red, those that are activated by GSK3 are depicted in green. Some substrates, such as p53 and NFκB, can be either activated or inhibited upon GSK3 phosphorylation, depending on the context. Substrates that undergo proteasomal degradation when phosphorylated by GSK3 are depicted in purple. Putative substrates are shown in gray.