Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury

Nathan, Fatima Megala; Ohtake, Yosuke; Wang, Shuo; Jiang, Xinpei; Sami, Armin; Guo, Hua; Zhou, Feng; Li, Shuxin

doi:10.1016/j.ymthe.2020.04.010

Cited by 46 publications

(31 citation statements)

References 81 publications

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“…For example, administering combinations of growth factors, including insulin growth factor 1 (IGF1) (Duan et al, 2015;Bei et al, 2016), interleukin-6 (IL-6) (Fischer, 2017), ciliary neurotrophic factor (CNTF) (Park et al, 2004;Leaver et al, 2006), and osteopontin (Bei et al, 2016;Anderson et al, 2018), stimulates regeneration of CNS axons. Other studies have shown that modulating distinct genes within the neurons, including signal transducers and activators of transcription factor 3 (Stat3) (Moore and Goldberg, 2011;Luo et al, 2016), histone deacetylase 5 (Hdac5) (Cho and Cavalli, 2012), Cacna2d2 (Tedeschi et al, 2016), Lin28a (Wang et al, 2018;Nathan et al, 2020), phosphatase and tensin homologue (Pten) (Park et al, 2008) or Kruppel like factors (Klfs) (Moore et al, 2009), can enhance neurons' intrinsic axon growth ability. Numerous studies have demonstrated that environmental factors also contribute to axon regeneration.…”

Section: Introductionmentioning

confidence: 99%

Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

Ribeiro

Levay

Yon

et al. 2020

eNeuro

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Growing axons in the central nervous system (CNS) often migrate along specific pathways to reach their targets. During embryonic development, this migration is guided by different types of cell adhesion molecules (CAMs) present on the surface of glial cells or other neurons, including the neural cadherin (NCAD). Axons in the adult CNS can be stimulated to regenerate, and travel long distances. Crucially, however, while a few axons are guided effectively through the injured nerve under certain conditions, most axons never migrate properly. The molecular underpinnings of the variable growth, and the glial CAMs that are responsible for CNS axon regeneration remain unclear. Here we used optic nerve crush to demonstrate that NCAD plays multifaceted functions in facilitating CNS axon regeneration. Astrocyte-specific deletion of NCAD dramatically decreases regeneration induced by PTEN ablation in retinal ganglion cells (RGCs). Consistent with NCAD's tendency to act as homodimers, deletion of NCAD in RGCs also reduces regeneration. Deletion of NCAD in astrocytes neither alters RGCs' mTORC1 activity nor lesion size, two factors known to affect regeneration. Unexpectedly however, we find that NCAD deletion in RGCs reduces PTEN-deletion induced RGC survival. We further show that NCAD deletion, in either astrocytes or RGCs, has negligible effects on the regeneration induced by ciliary neurotrophic factor (CNTF), suggesting that other CAMs are critical under this regenerative condition. Consistent with this notion, CNTF induces expression various integrins known to mediate cell adhesion. Together, our study reveals multilayered functions of NCAD and a molecular basis of variability in guided axon growth. 3 Significance Statement Growing axons often travel long distances and migrate along explicit pathways to reach their targets. Cell adhesion molecules (CAMs) including cadherins play vital roles in these processes during development. However, it remains unclear whether the same factors are involved for the adult axons after injury. This study used knockout mice to demonstrate that ablation of NCAD in astrocytes or retinal ganglion cells, prevents regeneration and cell survival induced by PTEN deletion. In contrary, NCAD deletion has negligible effects on the regeneration and survival induced by cytokines, suggesting that distinct CAMs control axon adhesion and growth under different regenerative conditions. Together, our study illustrates cadherins' versatile functions in the injured CNS, and points to distinct mechanisms that shape directed axon growth.

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Section: Introductionmentioning

confidence: 99%

Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

Ribeiro

Levay

Yon

et al. 2020

eNeuro

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“…Sox11, a TF belonging to the same family of Sox2, has also been shown to induce optic nerve and CST regeneration ( Wang et al., 2015 ; Norsworthy et al., 2017 ). Furthermore, our recent study ( Wang et al., 2018a ; Nathan et al., 2020 ) showed clearly that Lin28 acted to regulate both sensory axon regeneration and optic nerve regeneration in vivo . Another study ( Zhang et al., 2019 ) later confirmed that overexpression of Lin28 in RGCs was sufficient to induce optic nerve regeneration.…”

Section: Reprogramming Cns Neurons For Axon Regenerationmentioning

confidence: 92%

“…From the mechanistic point of view, the deletion of Mdm2/4 promoted axon regeneration by transactivating p53 and upregulated p53-dependent RAGs ( Joshi et al., 2015 ). Similar to c-Myc, Sox, and Klf families, which are well-known for their roles in regulation of cell lineage reprogramming, reprogramming factor Lin28 has been shown to induce significant axon regeneration after optic nerve or spinal cord injury ( Wang et al., 2018a ; Zhang et al., 2019 ; Nathan et al., 2020 ). Although it was not conducted in CNS sources, real-time qPCR revealed that Lin28 overexpression in mouse dorsal root ganglion (DRG) neurons upregulated genes c-Myc and ten-eleven translocation 3 (Tet3), two broad-spectrum epigenetic and transcriptional regulators shown related to axon regeneration ( Belin et al., 2015 ; Weng et al., 2017 ; Wang et al., 2018a ).…”

Section: Transcriptional Regulation Of Intrinsic Axon Regeneration Abmentioning

confidence: 99%

Updates and challenges of axon regeneration in the mammalian central nervous system

Qian

Zhou

2020

Journal of Molecular Cell Biology

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Axon regeneration in the mammalian central nervous system (CNS) has been a long standing and highly challenging issue. Successful CNS axon regeneration will benefit many human diseases involving axonal damage, such as spinal cord injury, traumatic brain injury, glaucoma, and neurodegenerative diseases. The current consensus is that the diminished intrinsic regenerative ability in mature CNS neurons and the presence of extrinsic inhibitors blocking axon regrowth are two major barriers for axon regeneration. During the past decade, studies targeting the intrinsic axon growth ability via regulation of gene transcription have produced very promising results in optic nerve and/or spinal cord regeneration. Manipulations of various signaling pathways or the nuclear transcription factors directly have been shown to sufficiently drive CNS axon regrowth. Converging evidence reveals that some pro-regenerative transcriptomic states, which are commonly accomplished by more comprehensive epigenetic regulations, exist to orchestrate the complex tasks of injury sensing and axon regeneration. Moreover, genetic reprogramming achieved via transcriptome and epigenome modifications provide novel mechanisms for enhancing axon regeneration. Recent studies also highlighted the important roles of remodeling neuronal cytoskeleton in overcoming the extrinsic inhibitory cues. However, our knowledge about the cellular and molecular mechanisms by which neurons regulate their intrinsic axon regeneration ability and response to extrinsic inhibitory cues is still fragmented. Here we provide an update about recent research progress in axon regeneration and discuss major remaining challenges for long distance axon regeneration and the subsequent functional recovery.

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“…Other intrinsic regenerative genes and pathways include Wnt signaling [114], Lin28 [115], Sry-related high-mobility-box 11 [116], Krüppel-like factor 4/9 [117], histone deacetylase [118], c-myc [119], and cAMP [93,120]. However, a single manipulation of these pathways or these genes is not enough for promoting long-lasting optic nerve regeneration in vivo.…”

Section: Intrinsic Survival and Regenerative Pathways For Optic Nerve Regenerationmentioning

confidence: 99%

The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

Oshitari

2021

IJMS

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Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.

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Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury

Cited by 46 publications

References 81 publications

Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

Updates and challenges of axon regeneration in the mammalian central nervous system

The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

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