Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

Franssen, Elske H.P.; Zhao, Rongrong; Koseki, Hiroaki; Kanamarlapudi, Venkateswarlu; Hoogenraad, Casper C.; Eva, Richard; Fawcett, James W.

doi:10.1523/jneurosci.2850-14.2015

Cited by 47 publications

(109 citation statements)

References 78 publications

(9 reference statements)

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“…The presence of mCherry allows visualisation of the entire axon. Anterograde transport was almost undetectable in control-transfected neurons where we observed predominantly retrograde and static vesicles ( Figure 6A and B), in keeping with previous studies (Franssen et al, 2015). Expression of p110δ triggered anterograde movement of integrins, leading to an increase in static integrin vesicles in the distal axon, and an overall increase in the total number of integrin vesicles ( Figure 6C).…”

Section: P110δ Enhances the Axonal Transport Of Regenerative Machinersupporting

confidence: 91%

“…Cells were transfected at 10 DIV, and experiments performed between DIV 14 and 17. Cortical neurons were transfected with magnetic nano-particles (Franssen et al, 2015).…”

Section: Embryonic Cortical Neuron Culturementioning

confidence: 99%

“…Axon transport analysis of integrins and Rab11 has been described in detail before Franssen et al, 2015). Briefly, Cortical neurons were transfected at DIV 10 with α9 integrin-GFP, or Rab11-GFP together with either mCherry (control) or mCherry plus p110δ, and imaged at DIV 14-16 DIV using spinning disc confocal microscopy.…”

Section: Analysis Of Neuronal Morphologymentioning

confidence: 99%

“…Conversely, peripheral nervous system (PNS) neurons maintain regenerative potential through adult life. This is partly because PNS neurons mount an injury response in the cell body (Puttagunta et al, 2014;Richardson et al, 1984;Richardson et al, 2009;Smith and Skene, 1997;Ylera et al, 2009), and partly because PNS axons support efficient transport of growth promoting receptors, whilst transport of these is developmentally downregulated in CNS axons Franssen et al, 2015;Gardiner et al, 2007;Hollis et al, 2009a;Hollis et al, 2009b). Studies into intrinsic regenerative capacity have implicated signalling molecules, transcription factors, epigenetic regulators, RNA binding proteins, and axon transport pathways as critical regeneration determinants (Blackmore et al, 2012;Fagoe et al, 2015;Hervera et al, 2019;Park et al, 2008;Tedeschi and Bradke, 2017;Weng et al, 2018;Zhang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Cells were transfected at 10 DIV, and experiments (imaging or axotomy) were performed between 14 and 17 DIV. Cortical neurons were transfected by oscillating nanomagnetic transfection (magnefect nano system, nanoTherics, Stoke-On-Trent, UK) as previously described(Franssen et al, 2015).hESC dopaminergic neuron culture RC17 hESC cell culture has been have been previously described in detail before(De Sousa et al, 2016;Koseki et al, 2017). Cells (RRID:CVCL_L206) were sourced from Roslin Cells, Scottish Centre for Regenerative Medicine, Edinburgh, United Kingdom.…”

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confidence: 99%

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

Barber

Evans

Nieuwenhuis

et al. 2019

Preprint

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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 found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110α and p110δ. Overexpressing p110α in CNS neurons had no effect, however expression of p110δ restored axonal PIP3 and enhanced CNS regeneration in rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion. KeywordsAxon, axon regeneration, CNS regeneration, optic nerve, neuronal signalling, phosphoinositide 3-kinase, PI3K, p110 delta, phosphatidylinositol(3,4,5)-trisphosphate, PIP3.

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Section: P110δ Enhances the Axonal Transport Of Regenerative Machinersupporting

confidence: 91%

“…Cells were transfected at 10 DIV, and experiments performed between DIV 14 and 17. Cortical neurons were transfected with magnetic nano-particles (Franssen et al, 2015).…”

Section: Embryonic Cortical Neuron Culturementioning

confidence: 99%

Section: Analysis Of Neuronal Morphologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Barber

Evans

Nieuwenhuis

et al. 2019

Preprint

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Axonal injury alters the extracellular glial environment of the axon initial segment and allows substantial mitochondrial influx into axon initial segment

Tamada

Kiryu‐Seo

Sawada

et al. 2021

J of Comparative Neurology

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The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra‐AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three‐dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non‐injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury.

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The Virtuous Cycle of Axon Growth: Axonal Transport of Growth‐Promoting Machinery as an Intrinsic Determinant of Axon Regeneration

Petrova

Eva

2018

Developmental Neurobiology

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Injury to the brain and spinal cord has devastating consequences because adult central nervous system (CNS) axons fail to regenerate. Injury to the peripheral nervous system (PNS) has a better prognosis, because adult PNS neurons support robust axon regeneration over long distances. CNS axons have some regenerative capacity during development, but this is lost with maturity. Two reasons for the failure of CNS regeneration are extrinsic inhibitory molecules, and a weak intrinsic capacity for growth. Extrinsic inhibitory molecules have been well characterized, but less is known about the neuron-intrinsic mechanisms which prevent axon re-growth. Key signaling pathways and genetic/epigenetic factors have been identified which can enhance regenerative capacity, but the precise cellular mechanisms mediating their actions have not been characterized. Recent studies suggest that an important prerequisite for regeneration is an efficient supply of growth-promoting machinery to the axon; however, this appears to be lacking from non-regenerative axons in the adult CNS. In the first part of this review, we summarize the evidence linking axon transport to axon regeneration. We discuss the developmental decline in axon regeneration capacity in the CNS, and comment on how this is paralleled by a similar decline in the selective axonal transport of regeneration-associated receptors such as integrins and growth factor receptors. In the second part, we discuss the mechanisms regulating selective polarized transport within neurons, how these relate to the intrinsic control of axon regeneration, and whether they can be targeted to enhance regenerative capacity. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

Cited by 47 publications

References 78 publications

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

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

Axonal injury alters the extracellular glial environment of the axon initial segment and allows substantial mitochondrial influx into axon initial segment

The Virtuous Cycle of Axon Growth: Axonal Transport of Growth‐Promoting Machinery as an Intrinsic Determinant of Axon Regeneration

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