Viral expression of constitutively active AKT3 induces CST axonal sprouting and regeneration, but also promotes seizures

Campion, Thomas J.; Sheikh, Imran S.; Smit, Rupert D.; Iffland, Philip H.; Chen, Jie; Junker, Ian P.; Krynska, Barbara; Crino, Peter B.; Smith, George M.

doi:10.1016/j.expneurol.2021.113961

Cited by 10 publications

(7 citation statements)

References 70 publications

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“…Phosphatase and tensin homolog (PTEN) is an important negative feedback regulator of PI3K–AKT signaling pathway blocking activation of the MAPK and PI3K–AKT signaling pathway ( 31 , 32 ). When we studied effects of FGFR inhibition on protein levels of PTEN in THP-1 cells, we found the phosphorylation level of PTEN was slightly increased in PD173074-treated group and THP-1-shRNA FGFR2 compared with controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10–FGFR2 signaling

Yu¹,

Ye²,

Wang³

et al. 2023

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10–FGFR2 signaling

Yu¹,

Ye²,

Wang³

et al. 2023

Journal of Biological Chemistry

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“…With the AAV1 mixture that we used, we observed on average 79.7% co-transduction at 12 weeks post-surgery and 68.92% at 16 weeks post-surgery, which indicated that this method was suitable for axon tracing (Fig.1A, B, C). It has been reported, that stimulating PI3K/pAkt/mTOR pathway with high titer vectors can lead to disproportionate soma size increases that were associated with several negative effects [18]. We therefore measured soma lengths of neurons in injured PI3K&[delta] treated rats and GFP controls.…”

Section: Resultsmentioning

confidence: 99%

Hyperactive PI3Kinase delta enables long distance regeneration of the rat corticospinal tract

Karova,

Polcanova,

Suchankova

et al. 2023

Preprint

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Maturation of central nervous system neurons leads to loss of their intrinsic regeneration potential. In particular after injury of the adult spinal cord there is minimal regeneration of corticospinal axons, which control gait and fine movement. Previous work has shown that knockdown of PTEN to increase PIP3 levels can promote regeneration in young animals, but the effect is much less in adults probably due to low PIP3 production. Here, we have transduced sensorimotor cortex neurons with a hyperactive form of PI3K, PI3Kδ, which increases PIP3 in mature neurons. This enables cortical neurons to regenerate corticospinal axons and improve behavioural outcomes.We used a C4 dorsal column lesion model in adult rats and injected the right motor cortex at 4 sites concurrently with a mixture AAV1-PIK3CD and AAV1-eGFP or titre matched AAV1-eGFP only. We allowed rats to survive for 6, 9, 12 or 16 weeks. Immunostaining showed 70 - 80% co-expression in cortical neurons which remained stable at both 12 and 16 weeks. We counted GFP labelled axons in 20 μm spinal cord sections. In PI3KCD-treated animals many axons were seen to have regenerated around the margins of lesions, collecting into a knot of axons with the typical appearance of regeneration at the caudal end. Tracing down the cord, and excluding axons and neurites that could have come from unlesioned ventral CST, we found axons extending up to 1 cm below lesions, numbers decreasing with distance from the lesion. After 16 weeks there were circa 200 axons at the caudal end of lesions with a regeneration index of 0.2, with half this number at 12 weeks. Behavioural testing for 16 weeks revealed functional improvements in skilled paw reaching, grip strength and ladder rung walking in rats treated with PIK3CD compared to GFP only controls. In addition to behavioural testing, functional recovery of PIK3CD treated rats was confirmed with electrophysiological recordings during which we stimulated the right pyramid. Cord dorsum potentials (CDPs) above and below lesion and EMG forepaw distal flexor muscles showed greatly increased connectivity compared with GFP only controls, lesion only controls and uninjured shams. We conclude that forcing upregulation of PI3Kδ in cortical neurons leads to robust regeneration after spinal cord injury that results in functional restoration.

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“…Moreover, the Sox2 component of that treatment, which is not expressed in injured or uninjured RGCs, is upregulated in the long-distance axon-regenerating RGCs that responded to Pten KD. Furthermore, several other known axon regeneration-promoting genes were also co-upregulated in the long-distance axon-regenerating RGCs by Pten KD, including Braf ( O'Donovan et al, 2014 ), Akt3 ( Campion et al, 2022 ), Igf1R ( Dupraz et al, 2013 ) and Sprr1a ( Bonilla et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Pten inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated Dynlt1a and Lars2

et al. 2023

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Central nervous system (CNS) projection neurons fail to spontaneously regenerate injured axons. Targeting developmentally regulated genes in order to reactivate embryonic intrinsic axon growth capacity, or targeting pro-growth tumor suppressor genes such as Pten, promotes long-distance axon regeneration in only a small subset of injured retinal ganglion cells (RGCs), despite many RGCs regenerating short-distance axons. A recent study identified αRGCs as the primary type that regenerates short-distance axons in response to Pten inhibition, but the rare types which regenerate long-distance axons, and cellular features that enabled such response, remained unknown. Here, we used a new method for capturing specifically the rare long-distance axon-regenerating RGCs, and also compared their transcriptomes to embryonic RGCs, in order to answer these questions. We found the existence of adult non-α intrinsically-photosensitive (ip) M1 RGC subtypes that retained features of embryonic cell state, and showed that these subtypes partially dedifferentiated towards an embryonic state and regenerated long-distance axons in response to Pten inhibition. We also identified Pten inhibition-upregulated mitochondria-associated genes, Dynlt1a and Lars2, which promote axon regeneration on their own, and thus present novel therapeutic targets.

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Viral expression of constitutively active AKT3 induces CST axonal sprouting and regeneration, but also promotes seizures

Cited by 10 publications

References 70 publications

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10–FGFR2 signaling

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10–FGFR2 signaling

Hyperactive PI3Kinase delta enables long distance regeneration of the rat corticospinal tract

Pten inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated Dynlt1a and Lars2

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