Optical control of ERK and AKT signaling promotes axon regeneration and functional recovery of PNS and CNS in Drosophila

Wang, Qin; Fan, Huaxun; Li, Feng; Skeeters, Savanna S.; Krishnamurthy, Vishnu V.; Song, Yuanquan; Zhang, Kai

doi:10.7554/elife.57395

Cited by 28 publications

(24 citation statements)

References 100 publications

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“…A report on axon regeneration after small peptide-induced inhibition of PTPσ indicated that extracellular regulated kinases (Erks) also are involved in regeneration of peripheral axons ( Yao et al, 2019 ). Another group of researchers specifically activated the ERK and Akt signaling pathways and performed a comprehensive study of neural regeneration in both PNS and CNS neurons in live Drosophila ( Wang et al, 2020 ). They found that both ERK and Akt activations enhanced axon regeneration in the sensory neurons in Drosophila larvae ( Wang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another group of researchers specifically activated the ERK and Akt signaling pathways and performed a comprehensive study of neural regeneration in both PNS and CNS neurons in live Drosophila ( Wang et al, 2020 ). They found that both ERK and Akt activations enhanced axon regeneration in the sensory neurons in Drosophila larvae ( Wang et al, 2020 ). These reports strongly suggest that Erk might be involved in the downstream signaling pathway after ChABC treatment.…”

Section: Discussionmentioning

confidence: 99%

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Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Rodemer

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI. However, due to the complexity of the mammalian CNS, it is still unclear whether this involves true regeneration or only collateral sprouting by uninjured axons, whether it affects the expression of CSPG receptors such as protein tyrosine phosphatase sigma (PTPσ), and whether it influences retrograde neuronal apoptosis after SCI. In the present study, we assessed the roles of CSPGs in the regeneration of spinal-projecting axons from brainstem neurons, and in the process of retrograde neuronal apoptosis. Using the fluorochrome-labeled inhibitor of caspase activity (FLICA) method, apoptotic signaling was seen primarily in those large, individually identified reticulospinal (RS) neurons that are known to be “bad-regenerators.” Compared to uninjured controls, the number of all RS neurons showing polycaspase activity increased significantly at 2, 4, 8, and 11 weeks post-transection (post-TX). ChABC application to a fresh TX site reduced the number of polycaspase-positive RS neurons at 2 and 11 weeks post-TX, and also reduced the number of active caspase 3-positive RS neurons at 4 weeks post-TX, which confirmed the beneficial role of ChABC treatment in retrograde apoptotic signaling. ChABC treatment also greatly promoted axonal regeneration at 10 weeks post-TX. Correspondingly, PTPσ mRNA expression was reduced in the perikaryon. Previously, PTPσ mRNA expression was shown to correlate with neuronal apoptotic signaling at 2 and 10 weeks post-TX. In the present study, this correlation persisted after ChABC treatment, which suggests that PTPσ may be involved more generally in signaling axotomy-induced retrograde neuronal apoptosis. Moreover, ChABC treatment caused Akt activation (pAkt-308) to be greatly enhanced in brain post-TX, which was further confirmed in individually identified RS neurons. Thus, CSPG digestion not only enhances axon regeneration after SCI, but also inhibits retrograde RS neuronal apoptosis signaling, possibly by reducing PTPσ expression and enhancing Akt activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Rodemer

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…PTEN/AKT pathway was previously implicated to play an important role in theregeneration of both axons and dendrites(Huang et al, 2019, Wang et al, 2020). The territory length and fusion phenomenaat 24h post-dendrotomywasnot affected in akt-1 mutant(Figure3 A-C) suggesting dendrite regeneration in PVD neurons is independent of akt-1 .…”

Section: Resultsmentioning

confidence: 99%

Dendrite regeneration in C. elegansis controlled by the RAC GTPase CED-10 and the RhoGEF TIAM-1

Brar

Dey

Bhardwaj

et al. 2021

Preprint

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Neurons are vulnerable to physical insults which compromise the integrity of both dendrites and axons. Although several molecular pathways of axon regeneration are identified, our knowledge of dendrite regeneration is limited. To understand the mechanisms of dendrite regeneration, we used PVD neurons in C. elegans having stereotyped branched dendrites. Using femtosecond laser, we severed the primary dendrites and axon of this neuron. After severing the primary dendrites near the cell body, we observed sprouting of new branches from the proximal site within 6 hours, which regrew further with time in an unstereotyped manner. This was accompanied by reconnection between the proximal and distal dendrites as well as the fusion among the higher-order branches as reported before. We quantified the regeneration pattern in three aspects territory length, number of branches and fusion phenomena. Axonal injury causes a retraction of the severed end followed by a Dual leucine zipper kinase-1 (DLK-1) dependent regrowth from the severed end. We tested the roles of the major axon regeneration signaling hubs such as DLK-1-RPM-1, cAMP elevation, let-7 miRNA, AKT-1, Phosphatidyl serine exposure/PS in dendrite regeneration. We found that neither regrowth nor fusion is affected by the axon injury pathway molecules. Surprisingly, we found that the RAC GTPase CED-10 and its upstream GEF TIAM-1 play a cell-autonomous role in dendrite regeneration. Additionally, function of CED-10 in epidermal cell is critical for post-dendrotomy fusion phenomena. This work describes a novel regulatory mechanism of dendrite regeneration and provides a framework for understanding the cellular mechanism of dendrite regeneration using PVD neuron as a model system.

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“…OptoRAF but not optoAKT induced neurite outgrowth in PC12 cells and sensory neuron dendrite branching in Drosophila larvae. Activation of optoRAF and optoAKT promoted axon regeneration in the peripheral and central nervous system in Drosophila indicating that these two subcircuits share some downstream components in neuroregeneration [ 74 ].…”

Section: Optogenetic Control Of Receptor Tyrosine Kinase Signalingmentioning

confidence: 99%

Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways

Kramer

Lataster

Weber

et al. 2021

IJMS

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Biological signals are sensed by their respective receptors and are transduced and processed by a sophisticated intracellular signaling network leading to a signal-specific cellular response. Thereby, the response to the signal depends on the strength, the frequency, and the duration of the stimulus as well as on the subcellular signal progression. Optogenetic tools are based on genetically encoded light-sensing proteins facilitating the precise spatiotemporal control of signal transduction pathways and cell fate decisions in the absence of natural ligands. In this review, we provide an overview of optogenetic approaches connecting light-regulated protein-protein interaction or caging/uncaging events with steering the function of signaling proteins. We briefly discuss the most common optogenetic switches and their mode of action. The main part deals with the engineering and application of optogenetic tools for the control of transmembrane receptors including receptor tyrosine kinases, the T cell receptor and integrins, and their effector proteins. We also address the hallmarks of optogenetics, the spatial and temporal control of signaling events.

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Optical control of ERK and AKT signaling promotes axon regeneration and functional recovery of PNS and CNS in Drosophila

Cited by 28 publications

References 100 publications

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Dendrite regeneration in C. elegansis controlled by the RAC GTPase CED-10 and the RhoGEF TIAM-1

Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways

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