Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

Abstract

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system. Axons in the central nervous system fail to regenerate, meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences. In 2008, genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve. PTEN is a phosphatase that opposes the actions of PI3-kinase, a family of enzymes that function to generate the membrane phospholipid PIP₃ from PIP₂ (phosphatidylinositol (3,4,5)-trisphosphate from phosphatidylinositol (4,5)-bisphosphate). Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase, and was initially demonstrated to promote axon regeneration by signaling through mTOR. More recently, additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability. This review describes neuronal signaling pathways downstream of PI3-kinase and PIP₃, and considers them in relation to both developmental and regenerative axon growth. We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability, and describe how these are affected by signaling through PI3-kinase. We highlight the recent finding of a developmental decline in the generation of PIP₃ as a key reason for regenerative failure, and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system. Finally, we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

Keywords: PI3-kinase; PI3K; PTEN; axon cytoskeleton; axon regeneration; axon transport; cell signaling; central nervous system; growth cone; neuroprotection; trafficking; transcription; translation.

Figure 1

Schematic of PI3-kinase and PIP₃ signaling. Regeneration-associated receptors activate intracellular enzymes including phosphoinositide 3-kinase (PI3K). PI3K converts PIP₂ into PIP₃, which in turn acts as a secondary messenger in multiple signaling cascades that influence axon growth and regeneration, among other important cellular functions. Phosphatase and tensin homolog (PTEN) is an important negative regulator of PI3K signaling by dephosphorylation of PIP₃ to PIP₂. The phosphates (P) on both phosphatidylinositols are shown in the schematic, in which the phosphate on the D3-position of PIP₃ is highlighted in green. PIP₃ generation recruits proteins with PH-, PX-, or FYVE domains to the plasma membrane and regulates their activity. The activation state of small GTPase Arf6 regulates axonal transport of regeneration-associated receptors, while small GTPases Cdc42 and Rac1 influence the cytoskeleton. The recruitment and activation of Akt by PIP₃ is well established. Akt activates mTOR and subsequently activates S6K1 and the phosphorylation of ribosomal protein S6. The mTOR complex also inactivates 4E-BP1, which in turn influences eIF-4E to regulate transcription and translation. Akt also inhibits GSK3 that activates transcription factor Smad1 and inhibits CRMP2, among the regulation of other proteins. Akt also influences the activation state of SSH1, which is upstream of ADF/cofilin, and Cortactin to regulate cytoskeleton dynamics.

Figure 2

PI3-kinase and neuron-intrinsic control of regenerative ability. This schematic summarises mechanisms downstream of PI3-kinase signaling that contribute to the axon regenerative ability of neurons.