Elsevier

Current Opinion in Neurobiology

Volume 27, August 2014, Pages 135-142
Current Opinion in Neurobiology

Signaling regulations of neuronal regenerative ability

https://doi.org/10.1016/j.conb.2014.03.007Get rights and content

Highlights

  • •

    Differential intrinsic regenerative ability of adult cortical neurons revealed by in vivo imaging analysis.

  • •

    Evolutionarily conserved pathways in regulating axon regeneration.

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    Functional interactions among different pathways in regulating axon regeneration.

Different from physiological axon growth during development, a major limiting factor for successful axon regeneration is the poor intrinsic regenerative capacity in mature neurons in the adult mammalian central nervous system (CNS). Recent studies identified several molecular pathways, including PTEN/mTOR, Jak/STAT, DLK/JNK, providing important probes in investigating the mechanisms by which the regenerative ability is regulated. This review will summarize these recent findings and speculate their implications.

Introduction

Similar to axon growth during development, axon regeneration requires the axonal extension guided by growth cone structures. This led to the hypothesis that similar principles and molecular players might operate these different processes. Ample evidence suggests that during development the extrinsic environmental cues largely determine the projection of axon growth, although the intrinsic states of responding neurons also modulate axonal responses [1]. For axon regeneration, dissecting the relative contributions of such extrinsic and intrinsic mechanisms has been a major focus in the past decades [2, 3, 4, 5, 6, 7, 8]. Early studies showed that reconstituting a permissive environment by transplanting peripheral nerve grafts allows the regrowth of some injured axons in the adult CNS, even though their numbers are limited [9, 10]. These observations have been further supported by elegant in vivo imaging-based analysis studies [11••, 12]. Canty et al. employed a focused laser method to transect individual axons, with minimal glial scar formation, in the gray matter of the adult mouse brain. Ylera et al. also demonstrated that central sensory axon lesion produced by two-photon laser in the spinal cord has minimal scar formation [12]. Again, while some types of axons in the brain could regenerate, the majority of injured axons fail to regrow even when visualized for periods of up to a year [11••]. These observations further substantiate the notion that the majority of mature neurons in the adult CNS have diminished intrinsic growth ability.

For a successful regeneration to occur, injured axonal terminals need to re-seal quickly and reform growth cone-like structure which will explore the extracellular environment, determine the direction of growth, and then guide the extension of the axon to the direction of their appropriate targets [13, 14, 15]. Presumably, the ability of injured axons to regenerate their growth cone structures and extend in injury-disturbed environments should represent the rate-limiting steps of axon regeneration. Recent genetic studies indicated that manipulating several signaling pathways could allow certain populations of mature CNS neurons to mount regenerative growth after injury and provide valuable molecular probes to explore the inner mechanisms of axon regeneration control in mammalian CNS neurons.

Section snippets

PTEN/mTOR: a general pathway of regulating axon regeneration?

All cell types possess certain molecular mechanisms that prevent cellular overgrowth, and many of these pathways have been implicated as tumor suppressors. In an effort to assess whether these growth suppressors play a role in limiting the intrinsic axon regenerative ability, Park et al. used an optic nerve injury model and discovered robust long-distance axon regenerations in adult mice with conditional deletion of the phosphatase and tensin homolog (PTEN) gene in retinal ganglion cells (RGCs)

mTOR as an indicator of regenerative competence?

The precise mechanisms by which PTEN/mTOR controls axon regeneration remain to be elucidated. Like other resting cells, intact mature neurons produce ATP mainly through catabolic processes to fuel the maintenance of energy-costly homoeostatic processes, such as cytoskeletal functions and ion and nutrient transport. However, for an injured neuron to initiate a regenerative growth, it has to shift toward anabolic processes, allowing for the de novo synthesis of macromolecules from available

Injury signals from the lesioned axons to neuronal soma

As neuronal networks are formed in the developing nervous system, axons progressively cease growing. Even in the adult CNS, transient sprouting could occur in the terminals of injured axons, likely as the result of local cytoskeleton rearrangements. To convert such abortive local events to sustained axon extension, a set of injury signals generated locally need to be retrogradely transported to the cell body and initiate injury responses (Figure 1). An important topic in the field is to

Signaling networks for integrated regenerative programs?

Differential injury responses in axotomized neurons should be the results of the interactions between the intrinsic neuronal state and the injury-triggered signals. As discussed above, JAK/STATs and DLK might participate in axotomy-triggered injury signal generation and delivery, and PTEN/mTOR might be a potential determinant of neuronal competence for axon regeneration (Figure 1). Recent studies start to reveal interactive mechanisms of these and other molecular pathways.

Kruppel-like factors

Perspectives

While these new studies demonstrated exciting possibilities of promoting the regeneration of injured axons in the adult CNS, many challenges remain toward translating these findings to therapeutic strategies. With dramatically increased body size in the adult, regenerating axons usually need to carry out de novo growth over relatively vast distances to reach their targets [94]. Even with these newly developed strategies of promoting axon regeneration, it is unclear what might be maximal

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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      Developing successful regenerative strategies for rewiring CNS axons is extremely important for neuroscience research. Both reduced intrinsic growth capability of developed neurons and extrinsic inhibitory environment around the lesion mainly attribute to the regeneration failure in adult mammals.55,56 Various signaling proteins controlled CNS neuronal survival and axon regeneration, including mTOR,6 STAT3,57 SOCS3,45,58 LKB1,43, KLFs,7,59 b-RAF,60 c-myc,10 SOX11,11,61 and osteopontin.62–64

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