A Novel Therapeutic Approach to Corneal Alkaline Burn Model by Targeting Fidgetin-Like 2, a Microtubule Regulator

Wang, Jessie; Dey, Abhinav; Kramer, Adam H.; Miao, Yuan; Liu, Juan; Baker, Lisa; Friedman, Joel M.; Nacharaju, Parimala; Chuck, Roy S.; Zhang, Cheng; Sharp, David J.

doi:10.1167/tvst.10.1.17

Cited by 6 publications

(9 citation statements)

References 41 publications

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“…In these experiments, we pooled 3 siRNA sequences targeting rat FL2 mRNA and encapsulated the siRNA into a nanoparticle formulation that has been used previously in other preclinical models to deliver siRNA to wounds ( 22 , 47 ). Efficacy of the formulation was confirmed in vitro in B35 cells (a rat neuroblastoma cell line) ( Supplemental Figure 9 ).…”

Section: Resultsmentioning

confidence: 99%

“…The migration of Schwann cells and the formation of these corridors across the nerve bridge is orchestrated by cell signaling between the Schwann cells and fibroblasts that accumulate in the gap following injury ( 67 ). As FL2 knockdown was found to increase directional cell migration ( 22 ) and enhance wound healing in other tissues ( 22 , 23 , 47 ), it is possible that treatment improves formation of new nerve tissue across transection gaps by enhancing directional migration of Schwann cells or other cells at the injury site and that these effects on nonneuronal cells in turn accelerate functional axon regeneration.…”

Section: Discussionmentioning

confidence: 99%

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Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration

Baker¹,

Tar²,

Kramer³

et al. 2021

JCI Insight

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The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axon regeneration and a therapeutic target for promoting nerve regeneration after injury. Genetic knockout of FL2 in cultured adult dorsal root ganglion (DRG) neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether FL2 could be targeted to promote regeneration in a rodent model of cavernous nerve (CN) injury. The CN are parasympathetic nerves that regulate blood flow to the penis, which are commonly damaged during radical prostatectomy (RP) resulting in erectile dysfunction (ED). Application of FL2-siRNA after CN injury significantly enhanced functional nerve recovery. Remarkably, following bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA, while no control treated animals exhibited regeneration. These studies identify FL2 as a promising therapeutic target for enhancing regeneration after peripheral nerve injury and for mitigating neurogenic ED post-RP-a condition for which, at present, only poor treatment options exist.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration

Baker¹,

Tar²,

Kramer³

et al. 2021

JCI Insight

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“…FL2 protein expression is minimal in adulthood but is significantly upregulated upon injury 26,[29][30][31] . FL2 protein is localized to the leading edge and cell cortex where FL2 carries out its severing function on dynamic microtubules during migration and outgrowth 29 .…”

Section: Fl2 Protein Was Upregulated After Injurymentioning

confidence: 99%

“…In neurons, FL2 depletion results in increased neurite outgrowth and an attenuated response to inhibitory cues during growth cone guidance 26 . Targeting of FL2 via siRNA mediated knockdown has shown promising results for multiple therapies, including enhanced excision and burn wound healing, nerve regeneration and regeneration after corneal chemical burn 26,[29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

mRNA Localization and Local Translation of the Microtubule Severing Enzyme, Fidgetin-Like 2, in Polarization, Migration and Outgrowth

Birnbaum

Biswas

Singer

et al. 2023

Preprint

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Cell motility requires strict spatiotemporal control of protein expression. During cell migration, mRNA localization and local translation in subcellular areas like the leading edge and protrusions are particularly advantageous for regulating the reorganization of the cytoskeleton. Fidgetin-Like 2 (FL2), a microtubule severing enzyme (MSE) that restricts migration and outgrowth, localizes to the leading edge of protrusions where it severs dynamic microtubules. FL2 is primarily expressed during development but in adulthood, is spatially upregulated at the leading edge minutes after injury. Here, we show mRNA localization and local translation in protrusions of polarized cells are responsible for FL2 leading edge expression after injury. The data suggests that the RNA binding protein IMP1 is involved in the translational regulation and stabilization of FL2 mRNA, in competition with the miRNA let-7. These data exemplify the role of local translation in microtubule network reorganization during migration and elucidate an unexplored MSE protein localization mechanism.

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“…Numerous studies on nanotechnology for corneal injury have emerged. It has been reported that dipotassium glycyrrhizinate-micelle formulation encapsulating active agents ( Hou et al, 2021 ), nanoparticle-encapsulated Fidgetin-like 2 siRNA ( Jessi Wang et al, 2021 ), and high-density lipoprotein nanoparticles with a gold nanoparticle core ( Lavker et al, 2021 ) showed promising results in accelerating corneal re-epithelialization and anti-inflammation. In addition, poly (lactic-co-glycolic acid) nanoparticles could be a drug release system of Lingzhi to reduce oxidative damage in corneal epithelium cells ( Tsai et al, 2021 ).…”

Section: Treatmentmentioning

confidence: 99%

Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies

Zhou

Lee

et al. 2022

Front. Pharmacol.

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Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.

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A Novel Therapeutic Approach to Corneal Alkaline Burn Model by Targeting Fidgetin-Like 2, a Microtubule Regulator

Cited by 6 publications

References 41 publications

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration

mRNA Localization and Local Translation of the Microtubule Severing Enzyme, Fidgetin-Like 2, in Polarization, Migration and Outgrowth

Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies

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