Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Bei, Fengfeng; Lee, Henry H.C.; Li, Xuefeng; Gunner, Georgia; Jin, Hai; Ma, Long; Wang, Chen; Hou, Lingling; Hensch, TakaoÂ K.; Frank, Eric; Sanes, JoshuaÂ R.; Chen, Chinfei; Fagiolini, Michela; He, Zhigang

doi:10.1016/j.cell.2015.11.036

Cited by 219 publications

(174 citation statements)

References 58 publications

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“…We next evaluated whether treatment with HDAC3 inhibitors after nerve injury would enhance remyelination and functional recovery of nerve conduction, which depends on the myelination state 5,25 . We performed sciatic nerve transection of the right hindlimb in a group of 8-week-old adult mice and then treated these mice with an HDAC3 inhibitor, either RGFP966 or PDA106 at a dose that resulted in effective inhibition of HDAC3 activity without adverse effects daily over the first week and every 2 d during the second week for a total of 3 d 21,26,27 .…”

Section: Resultsmentioning

confidence: 99%

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A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Zhang

Queme

et al. 2018

Nat Med

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Deficits in Schwann cell–mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin–PI3K–AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell–specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3–TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

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Section: Resultsmentioning

confidence: 99%

“…Functional regeneration and recovery after nerve injury requires not only axonal regrowth but also remyelination of the regenerated axons 5,25 . Despite the remarkable axonal regeneration capacity of peripheral nerves, myelin sheaths regenerated after injury are substantially thinner than myelin formed during development 4,5 .…”

Section: Discussionmentioning

confidence: 99%

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Zhang

Queme

et al. 2018

Nat Med

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“…Interestingly, several combinatory approaches have been shown to be able to promote axon regeneration after injury (62,63). However, interventions for multiple targets make clinical applications difficult.…”

Section: Discussionmentioning

confidence: 99%

Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury

Ding

Chu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

113

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Remodeling of cytoskeleton structures, such as microtubule assembly, is believed to be crucial for growth cone initiation and regrowth of injured axons. Autophagy plays important roles in maintaining cellular homoeostasis, and its dysfunction causes neuronal degeneration. The role of autophagy in axon regeneration after injury remains speculative. Here we demonstrate a role of autophagy in regulating microtubule dynamics and axon regeneration. We found that autophagy induction promoted neurite outgrowth, attenuated the inhibitory effects of nonpermissive substrate myelin, and decreased the formation of retraction bulbs following axonal injury in cultured cortical neurons. Interestingly, autophagy induction stabilized microtubules by degrading SCG10, a microtubule disassembly protein in neurons. In mice with spinal cord injury, local administration of a specific autophagy-inducing peptide, Tat-beclin1, to lesion sites markedly attenuated axonal retraction of spinal dorsal column axons and cortical spinal tract and promoted regeneration of descending axons following long-term observation. Finally, administration of Tat-beclin1 improved the recovery of motor behaviors of injured mice. These results show a promising effect of an autophagyinducing reagent on injured axons, providing direct evidence supporting a beneficial role of autophagy in axon regeneration.autophagy | microtubule stabilization | axon regeneration I t is generally believed that the inability of adult central nervous system (CNS) neurons to regenerate their axons following injury is due to the presence of abundant inhibitory factors in extrinsic milieu and the lack of intrinsic growth ability (1-5). A number of extrinsic growth-inhibitory factors have been identified, including oligodendrocyte-derived myelin-associated glycoprotein (MAG), Nogo, OMgp, or astrocyte-derived chondroitin sulfate proteoglycans (CSPGs), which act through their respective receptors to suppress axon growth and regeneration (6-11). However, genetic ablation or elimination of these inhibitory receptors does not promote axon regeneration (12, 13) or shows marginal effects (14, 15).Many inhibitory factors act through signaling cascades to modulate cytoskeletal dynamics (16,17). Indeed, it has been observed that CNS axons form numerous retraction bulbs (RBs) with a disorganized array of microtubules (MTs), whereas peripheral nervous system (PNS) axons rapidly form a growth cone with stable, well-organized bundling of MTs following injury (18). In line with this notion, pharmacological stabilization of MTs promotes axon regeneration after spinal cord injury (SCI) (19,20). In addition, analyses of gene-targeted mice have led to identification of several intrinsic inhibitors of axon regeneration in the adult CNS, including phosphatase and tensin homolog (PTEN) and the suppressor of cytokine signaling 3 (SOCS3) (21,22). However, manipulating individual proteins or in combinations allows limited axonal regeneration or sprouting, which is usually associated with temporary improvement ...

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“…There, it has been found that RGC axons can be stimulated to correctly reinnervate the superior colliculus by either a PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin, insulin-like growth factor 1 (IGF-1), and CNTF. Although these treatments enable the formation of functional synapses, recovery of visual function requires additional stimulation of axon potentials conduction within the still unmyelinated axons, which can be achieved via the administration of voltage-gated potassium channel blockers (Bei et al 2016).…”

Section: Models and Methods To Induce Optic Nerve Regenerationmentioning

confidence: 99%

“…Significant, but not yet complete recovery of the OMR has been achieved after optic nerve injury followed by growth-stimulating treatments (de Lima et al 2012;Lim et al 2016). Of note, restoration of the OMR has also been shown in the optic tract transection model, after regenerative treatment that included PTEN deletion (Bei et al 2016). This behavioral assay could thus serve as an alternative model to study functional recovery.…”

Section: Vision-driven Behavioral Tests In Rodentsmentioning

confidence: 97%

Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

et al. 2017

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Due to the lack of axonal regeneration, age-related deterioration in the central nervous system (CNS) poses a significant burden on the wellbeing of a growing number of elderly. To overcome this regenerative failure and to improve the patient's life quality, the search for novel regenerative treatment strategies requires valuable (animal) models and techniques. As an extension of the CNS, the retinofugal system, consisting of retinal ganglion cells that send their axons along the optic nerve to the visual brain areas, has importantly contributed to the current knowledge on mechanisms underlying the restricted regenerative capacities and to the development of novel strategies to enhance axonal regeneration. It provides an extensively used research tool, not only in amniote vertebrates including rodents, but also in anamniote vertebrates, such as zebrafish. Indeed, the latter show robust regeneration capacities, thereby providing insights into the factors that contribute to axonal regrowth and proper guidance, complementing studies in mammals. This review provides an integrative and critical overview of the classical and state-of-the-art models and methods that have been employed in the retinofugal system to advance our knowledge on the signaling pathways underlying the restricted versus robust axonal regeneration in rodents and zebrafish, respectively. In vitro, ex vivo and in vivo models and techniques to improve the visualization and analysis of regenerating axons are summarized. As such, the retinofugal system is presented as a valuable model to further facilitate research on axonal regeneration and to open novel therapeutic avenues for CNS pathologies.

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Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Cited by 219 publications

References 58 publications

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury

Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

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