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

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

Bart Nieuwenhuis , Richard Eva PhD 
John van Geest Center for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

Date of Submission	10-Mar-2021
Date of Decision	24-Apr-2021
Date of Acceptance	02-Jun-2021
Date of Web Publication	12-Nov-2021

Correspondence Address:
Richard Eva
John van Geest Center for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge
UK

Source of Support: This work was funded by the Medical Research Council (MR/R004544/1, MR/R004463/1, to RE), EU ERA-NET NEURON (AxonRepair grant, to BN), Fight for Sight (5119/5120, and 5065-5066, to RE), and National Eye Research Centre (to RE), Conflict of Interest: None

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DOI: 10.4103/1673-5374.327324

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

How to cite this article: Nieuwenhuis B, Eva R. Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling. Neural Regen Res 2022;17:1172-82

How to cite this URL: Nieuwenhuis B, Eva R. Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling. Neural Regen Res [serial online] 2022 [cited 2021 Nov 16];17:1172-82. Available from: http://www.nrronline.org/text.asp?2022/17/6/1172/327324

Introduction

Class I phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that mediate signaling downstream of growth factor-, cytokine-, and integrin receptors, by producing the membrane phospholipid PIP₃ from PIP₂ (phosphatidylinositol (3, 4, 5)-trisphosphate from phosphatidylinositol (4,5)-bisphosphate). Activation of PI3K is the first step in a well-characterized signaling pathway that regulates a wide range of cellular functions including growth, survival and motility (Vanhaesebroeck et al., 2012). In the nervous system, it has long been implicated in the regulation of axonal specification and elongation during development (Cosker and Eickholt, 2007), and was identified in 2008 as a key pathway that could be targeted to support axon regeneration in the adult central nervous system (CNS), through genetic deletion of the enzyme PTEN (Park et al., 2008). PTEN functions to oppose the actions of PI3K. These ground-breaking studies led to a research focus on the PI3K/PTEN pathway, aimed at identifying potentially translatable approaches that might enable repair of injured axons in the adult CNS. These studies have been enormously beneficial in highlighting the importance of this pathway and identifying potential approaches for treating CNS injuries (Zhang et al., 2018).

A more recent study focused on increasing regeneration through hyperactivation of PI3K, as opposed to deletion of PTEN (Nieuwenhuis et al., 2020). This study identified additional cell biological mechanisms through which PI3K enables axon growth, not only during development, but also during regeneration after injury in the adult CNS. The study confirms PIP₃ as a key lipid for growth cone redevelopment and axon regeneration, and demonstrates a developmental decline in axonal PIP₃ as a key reason behind axon regeneration failure in the adult CNS. In this review, we summarize the neuronal signaling pathways that function downstream of PI3K and its product phosphatidylinositol(3, 4, 5)-trisphosphate (PI3, 4, 5P or PIP₃) in relation to axon growth. We discuss the neuron-intrinsic mechanisms that determine the regenerative ability of axons in the adult CNS, and describe how many of these are affected by PI3K activation. We highlight that a key factor for regenerative failure is the developmental decline in PI3K and PIP₃, and summarize the studies that have targeted an increase in signaling downstream of PI3K/PTEN as a means of facilitating regeneration in the adult CNS. Finally, we discuss the need for further work, and the obstacles that need to be overcome in order to generate a clinically useful strategy for repairing the injured CNS through PI3K manipulation.

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