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PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.

ABSTRACT: Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110? and p110?. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110? in CNS neurons had no effect; however, expression of p110? restored axonal PIP3 and increased regenerative axon transport. p110? expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110?. Furthermore, viral delivery of p110? promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110? facilitates axon regeneration by functioning in a hyperactive fashion.

SUBMITTER: Nieuwenhuis B

PROVIDER: S-EPMC7411663 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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PI 3-kinase delta enhances axonal PIP<sub>3</sub> to support axon regeneration in the adult CNS.

Nieuwenhuis Bart B Barber Amanda C AC Evans Rachel S RS Pearson Craig S CS Fuchs Joachim J MacQueen Amy R AR van Erp Susan S Haenzi Barbara B Hulshof Lianne A LA Osborne Andrew A Conceicao Raquel R Khatib Tasneem Z TZ Deshpande Sarita S SS Cave Joshua J Ffrench-Constant Charles C Smith Patrice D PD Okkenhaug Klaus K Eickholt Britta J BJ Martin Keith R KR Fawcett James W JW Eva Richard R

EMBO molecular medicine 20200617 8

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP<sub>3</sub> ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in ...[more]

PMID: 32558386

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Project description:The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENT Restoration of neurologic function after spinal cord injury has yet to be achieved in human patients. To accomplish this, severed nerve fibers must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently, a method for stimulating long-distance axon regeneration of sensory fibers in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration program which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum (ER). The study identifies mechanisms that neurons need to activate to regenerate their nerve fibers.

Dataset Information

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.

Publications

PI 3-kinase delta enhances axonal PIP<sub>3</sub> to support axon regeneration in the adult CNS.

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