Lin28 Signaling Supports Mammalian PNS and CNS Axon Regeneration

Wang, Xue-Wei; Li, Qiao; Liu, Chang Mei; Hall, Phil; Jiang, Jing; Katchis, Christopher D.; Kang, Sehwa; Dong, Bryan; Li, Shuxin; Zhou, Feng

doi:10.1016/j.celrep.2018.07.105

Cited by 108 publications

(132 citation statements)

References 57 publications

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“…1A). The fixed optic nerves were first tissue cleared to be transparent as previously described ( 12 ) and then axons were imaged with confocal microscopy. The results showed that very limited optic nerve regeneration occurred in wild type mice infected with AAV2-Cre.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent study showed that overexpression of Lin28 in RGCs induced robust and sustained optic nerve regeneration via regulation of gene expression and enhanced intrinsic axon regeneration ability ( 12 ). Therefore, we tested if combining myosin IIA/B dKO, which alters axonal cytoskeletal dynamics, with Lin28 overexpression, which controls gene expression, could have combinatory promoting effect on optic nerve regeneration.…”

Section: Resultsmentioning

confidence: 99%

“…2A, B). Because the dehydration process in the tissue clearing approach results in 18% of shrinkage in nerve lengths ( 12 ), the real lengths of the longest regenerating axons were more than 4 mm. Indeed, in about half of nerves in the combinatory group the longest regenerating axons almost reached the optic chiasm (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To test this idea, we examined how myosin IIA/B dKO affected two well-known pathways governing the intrinsic axon regeneration ability, the activation of mTOR, marked by increased level of phospho-S6 (pS6), and the inactivation of GSK3β, marked by phosphorylation of its serine 9 residue (pGSK3β), at 2 weeks after ONC. Previous studies have shown that most identified molecules promoting optic nerve regeneration act via either of these pathways, including Pten knockout ( 9 ), Akt overexpression ( 22, 23 ), Lin28 overexpression ( 12 ), osteopontin overexpression ( 24 ), SOCS3 deletion ( 10 ), melanopsin overexpression ( 25 ), HDAC5 manipulation ( 26 ), and direct modulation of mTOR ( 27 ) or GSK3β signaling ( 22 ). For mTOR activation, we examined the level of pS6 in RGCs under different conditions.…”

Section: Resultsmentioning

confidence: 99%

“…The results showed that deleting myosin IIA/B alone was sufficient to induce robust and sustained optic nerve regeneration. Moreover, combination of myosin IIA/B knockout and Lin28 overexpression, which enhances the intrinsic axon regeneration ability of RGCs ( 12 ), led to synergistic promoting effect and long-distance optic nerve regeneration. Importantly, the promoting effect was independent of well-known signaling mediators of optic nerve regeneration, such as increased mTOR activity and GSK3β inactivation ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

Wang

Yang

Zhang

et al. 2019

Preprint

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23In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another 24 key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here we showed that 25 knocking out myosin IIA/B in retinal ganglion cells alone either before or after optic nerve crush induced 26 marked and sustained optic nerve regeneration. Combined Lin28 overexpression and myosin IIA/B 27 knockout led to synergistic promoting effect and long-distance axon regeneration. Immunostaining, RNA-28 seq and western blot analyses revealed that myosin II deletion did not affect known axon regeneration 29 signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction 30 bulb formation and significantly enhanced the axon extension efficiency. The study provided clear 31 evidence that directly targeting neuronal cytoskeleton was sufficient to induce strong CNS axon 32 regeneration, and combining gene expression in the soma and modified cytoskeletal dynamics in the axon 33 was a promising approach for long-distance CNS axon regeneration. 34 35 Keywords 36Axon regeneration, optic nerve regeneration, non-muscle myosin II, Lin28, growth cone, cytoskeleton 37 38 42 hostile environment created by inhibitors in the scar tissues and degenerating myelin, and the other is the 43 diminished intrinsic neural regeneration ability of mature CNS neurons (1, 2). Therefore, the widely 44 accepted view is that combination strategies that target both intrinsic growth ability and inhibitory 45 environment are likely the best option for successful CNS axon regeneration and function recovery. Early 46 studies (3-6) using peripheral nerve graft transplants have shown that some mature CNS neurons, such as 47 spinal cord neurons and retinal ganglion cells (RGCs), could regenerate their axons into the permissive 48 nerve grafts, indicating clearly that these neurons still retain limited intrinsic regeneration ability. However, 49 to date, many studies targeting selected inhibitory molecules resulted in no or very modest CNS 50 regeneration (7, 8). A likely reason is that there are multiple classes of inhibitory molecules, potentially 51 including unidentified ones, which inhibit axon regeneration via distinct cellular and molecular 52 mechanisms. Thus, targeting a few inhibitory signals while leaving the others intact may not result in a 53 permissive environment similar to that in the peripheral nerve grafts. 54In contrast, studies targeting the intrinsic axon growth ability have produced very promising results. 55In the optic nerve regeneration model, for example, Pten, Socs3, Klf4 loss of function, and Lin28 gain of 56 function all achieved strong optic nerve regeneration (9-13). However, tissue clearing and 3D imaging 57 studies have revealed that many of the regenerating RGC axons make U-turns in the optic nerve, at the 58 optic chiasm, or make wrong guidance decisions after the chiasm (14, 15). In the corticospinal tract (CST) 59 regeneration model, although modulation of the in...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

Wang

Yang

Zhang

et al. 2019

Preprint

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Lnc‐Pim1 Promotes Neurite Outgrowth and Regeneration of Neuron‐Like Cells Following ACR‐Induced Neuronal Injury

Li,

Jiang,

Tang

et al. 2024

J of Cellular Biochemistry

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Decreased regenerative capacity of central nervous system neurons is the main cause for failure of damaged neuron regeneration and functional recovery. Long noncoding RNAs (lncRNAs) are abundant in mammalian transcriptomes, and many time‐ and tissue‐specific lncRNAs are thought to be closely related to specific biological functions. The promoting effect of Pim‐1 gene on neural differentiation and regeneration has been documented, but the effect and mechanism of its neighbor gene Lnc‐Pim1 in regulating the response of central neurons to injury remain unclear. RT‐PCR in this study demonstrated that the expression of Lnc‐Pim1 was upregulated in acrylamide (ACR)‐induced neuronal injury. FISH and nucleus‐cytoplasmic assay demonstrated that Lnc‐Pim1 was mainly expressed in the neuron cytoplasm, with a small amount in the nucleus. Western blot analysis proved that Lnc‐Pim1 overexpression induced by the lentivirus vector could promote neurite outgrowth in Neuro‐2a cells by activating the Erk1/2 signal pathway, and improve neurite regeneration of injured neurons by upregulating GAP‐43 and β‐Ⅲ tubulin protein expression. However, silencing Lnc‐Pim1 expression by interfering RNA could effectively downregulate the GAP‐43 and β‐Ⅲ tubulin protein expression, and inhibit neurite growth of neurons. In addition, CHIRP‐MS was performed to identify several potential targets of Lnc‐Pim1 involved in the regulation of neurite regeneration of injured neurons. In conclusion, our study demonstrated that Lnc‐Pim1 is a potential lnc‐RNA, playing an important role in regulating central nerve regeneration.

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Comparing axon regeneration in male and female mice after peripheral nerve injury

Jang

Bae

Yang

et al. 2021

J of Neuroscience Research

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Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration‐associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real‐time reverse transcription polymerase chain reaction. Furthermore, the RNA‐seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham‐operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex‐dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.

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Lin28 Signaling Supports Mammalian PNS and CNS Axon Regeneration

Cited by 108 publications

References 57 publications

Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

Lnc‐Pim1 Promotes Neurite Outgrowth and Regeneration of Neuron‐Like Cells Following ACR‐Induced Neuronal Injury

Comparing axon regeneration in male and female mice after peripheral nerve injury

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