Up the distal stump (PNS), axonal sprouts

Up until recently,
it was thought impossible for neurons of the CNS to have the ability to
regenerate. Thanks to advances in medicine, the mechanisms underlying the
differences in axonal regeneration between the central nervous system (CNS) and
peripheral nervous system (PNS), have become evident, and so it’s been revealed,
that neurons of the CNS can regenerate (in vitro), leading to the belief in
vivo regeneration is possible. It was work in axotomy that revealed that
neurons of the CNS don’t naturally regenerate and that there was some
regeneration in the PNS.1 This essay will be split into three main
sections: first, I’ll be exploring the fundamental differences between CNS and
PNS axon regeneration. Second, I aim to outline the molecular and cellular
mechanisms that account for these differences, and finally, I’ll attempt to
give an account for why these differences may have developed.

What are the differences in axon
regeneration following injury between the central and peripheral nervous

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Overall, there’s no
functional regeneration of axons within the CNS, whereas there is some
regeneration of axons in the PNS.1
In the CNS, proximal
stumps will start to regenerate a few millimetres, however the axons sprout
into the lesion, causing them to stall and form retraction bulbs. On the other
hand, the proximal stumps in the PNS will bypass the lesion; regrowth is
vigorous and long-distance.2,4,10 A significant number of sprouting axons
(PNS) will enter neurilemmal tubes, these lead to motor or sensory terminals,
restoring some function.3 Oligodendrocytes are the cells responsible for
myelinating CNS neurons, and Schwann cells are responsible for myelinating PNS
neurons.1 Figure 1 shows how PNS axons are able to regenerate whereas CNS
axons aren’t.

Figure 1 – comparing axon regeneration
between the CNS and PNS 19



Following Wallerian
degeneration of the distal stump (PNS), axonal sprouts from the proximal
segment will enter the distal portion of the neuron and will grow along the
nerve until reaching its target. Schwann cells are responsible for attracting
axons to the distal stump, as well as remyelinating axons after new, functional
nerve endings have been formed.10Schwann cells align in tubes known as Bünger
bands and express surface molecules that guide regenerating fibres. They also fill
the endoneurial tube at the cut end.9,12 Oligodendrocytes die after CNS
injury, meaning they can’t remyelinate axons.1 Essentially, there’s two
reparative mechanisms occurring simultaneously in the PNS. Branchlets extend
distally from the distal stump, the tips of these branchlets are known as
growth cones. In the distal stump, Schwann cells will send processes in the direction
of the cones. The cones develop surface receptors that will anchor to
complementary cell surface adhesion molecules on the basement membrane of
Schwann cells. Filaments of actin surmounted on the cones become attached to
these points of anchorage, where they’re able to exert onward traction on the
growth cones.13 This process allows for axons of the PNS to grow roughly at a
rate of 3-4mm/day after injury.9 More chromatolysis occurs in neurons found
within the CNS and the PNS neurons survive the process with greater efficacy;
chromatolysis occurs near the nucleus of the neurons found within the CNS and
the periphery of neurons found within the PNS.4 Overall, the differences
could be summarised in a simplistic manner: there’s no functional regeneration
of axons within the CNS following injury whilst there is some functional
regeneration within the PNS.

Describe the molecular and
cellular mechanisms underlying these differences

It’s fair to say
that it’s an interplay of mechanisms that contribute to these differences.1
The ineffective and aggressive immune response seen in the CNS following injury
is a massive contributing factor to the lack of axon regeneration. The biggest
inhibitor of axon regeneration following injury in the CNS, is the formation of
non-permissive glial scarring.1,13 ECM glial scarring is the result of a
glial reaction that recruits microglia, oligodendrocyte precursors, meningeal
cells and astrocytes.1 Chondroitin sulfate proteoglycans (CSPGs) are the main
inhibitory molecules found in glial scars, CSPGs are upregulated by reactive
astrocytes following CNS damage.4 A review of CSPGs demonstrated that after
CNS injury, CSPG expression was increased, indicating this increased expression
contributes to the non-permissive nature of glial scarring.5 It’s also been
reported that CSPGs’ inhibitory action can be reduced by the enzyme
Chondroitinase ABC (ABC); ABC cleaves glycosaminoglycan side chains attached to
core proteins, further revealing the non-permissive nature of CSPGs in axon
regeneration.4 ECM glial scarring not only provides a physical barrier for
axonal sprouting, but a biochemical one as well, contributing to the cytotoxic
environment.1 Figure 2 shows the non-permissive nature of glial scarring, as
well as the components of the scar. It’s visible that the scar acts as a
physical and biochemical barrier to regenerating axons.                                 


Figure 2 – non-permissive
glial scar surrounding fluid filled cavity 17

 The highly vascularised CNS means that a large
influx of immune cells occurs following injury, immune cells contributing to
the non-permissive environment. Cytokines also contribute to inflammation. The
debris produced following injury proves toxic to macrophages that aren’t able
to clear the debris and migrate, like they do in the PNS. The macrophages then
turn into foam cells as they aren’t able to break down myelin lipid, adding to
the inflammation about the injury.1 It’s understood that CNS axons are able
to regenerate when in a permissive environment, indicating that it’s the
non-permissive environment above all else that inhibits axon regeneration in
the CNS, following injury. Oligodendrocytes express myelin-associated
inhibitors, a component of myelin that has been shown to impair in vitro
neurite growth, and are believed to do the same in vivo, following injury. This
class of inhibitor includes but isn’t limited to Nogo-A, myelin-associated
glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp). MAG gets
cleared away rapidly in the PNS but not in the CNS. Nogo-A interacts with the
Nogo-66 receptor to inhibit axon growth, Nogo-A isn’t normally seen in the PNS.4
The CNS has an inadequate pattern of expression of  neurotrophic growth factors for axon
growth.1 The environment following injury in the PNS is conducive for
regeneration; the immune response is fast and effective and is able to clear
the debris; there’s no inflammation or cytotoxicity. Schwann cells are better
myelinators than oligodendrocytes, and they produce many growth factors.1
Studies indicate that Schwann cell migration to facilitate elongation of axons
is mainly driven by neurotrophic growth factors like NGF, or by cytokines and
laminin, highlighting the importance of the molecular interactions between Schwann
cells and its environment.8 After PNS axotomy, neurons up-regulate
regenerative-associated genes (RAGs), they activate transcription factors that
produce growth-associated proteins. Over-expression of these genes has been
shown to cause neurite outgrowth. CNS neurons don’t express these genes in the
same manner.4 Figure 3 highlights the importance of RAGs and the
myelin-associated inhibitors of Oligodendrocytes in axon regeneration/lack of

Figure 3 – differences
in molecular and cellular responses seen in the PNS and CNS following injury


Along with this,
neurotrophins and cell-adhesion molecules are up-regulated following
axotomy.9 Neurotrophins act as dimers that activate downstream signalling
pathways that activate RAGs, promoting survival.11 Overall, the differences
in the mechanisms can be understood when looking at a range of contributing
factors, ranging from production of growth factors, permissive/non-permissive
environments and even regulation of gene transcription.

Why may such differences have

During early,
post-natal life, brain circuitry is remodelled in accordance with experience,
so we’re able to adapt to the challenges of the world. It’s important for the
brain to stabilise, so that constancy can be maintained when we’re exposed to
small changes in the environment; we don’t want brain remodelling in all
instances.10. Studies have highlighted parallels between mechanisms
preventing axonal repair and those that limit experience-dependent plasticity.
14 Earlier it was mentioned the Nogo receptor pathway inhibits axonal
regeneration; the pathway also restricts adult neural plasticity.15 It’s been
observed that supressing nogo receptor signalling enhances neural repair; it
can be inferred neural repair involves plasticity.16 Perhaps limited CNS
regeneration is a price to pay for higher intellectual capabilities.10


In conclusion, axon
regeneration/lack of regeneration is a complex process that involves an
interplay of molecular and cellular processes. Axons of the CNS will only
sprout a few millimetres, resulting in a lack of functional regeneration in the
CNS. It was discussed how the most important inhibitor of axon regeneration is
the formation of non-permissive, glial scarring, which amongst other factors,
contributes to a non-permissive environment for axon regeneration. Experimental
data has revealed that axons of the CNS have the ability to regenerate in the
right environment. Axons of the PNS are able to regenerate so that some
functionality is recovered following injury in the PNS. Axon regeneration is
possible as the environment in the PNS is permissive for axons to sprout around
the lesion and form new connections at terminals. Growth factors, produced by
Schwann cells, are more abundant in the PNS, and Schwann cells are better
myelinators than oligodendrocytes (found in CNS). Accounting for these
differences is best understood when exploring the mechanisms of
neuroplasticity, and seeing how there is an overlap in the mechanisms that
limit axon regeneration and those that limit experience-dependent plasticity.