What underlying the differences in axonal regeneration between the

What are the differences in axon regeneration
following injury between the central and peripheral nervous systems? Describe
the molecular and cellular mechanisms underlying these differences. Why may
such differences have developed?



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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 axons of the CNS can regenerate (in vitro), leading to the belief in vivo
regeneration is possible. It was work in axotomy that revealed that axons 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

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.2,3,4 A significant number of sprouting axons
(PNS) will enter neurilemmal tubes, these lead to motor or sensory terminals,
restoring some function.5 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 can only sprout a short-distance.

Figure 1 – comparing axon regeneration
between the CNS and PNS6



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.4Schwann 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.7,8 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.9 This process allows for axons of the PNS to
grow roughly at a rate of 3-4mm/day after injury.7 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.3 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

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.1,9 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.3 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.10 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.3 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 cavity11

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.3 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.12 After PNS axotomy, neurons up-regulate
regenerative-associated genes (RAGs), they activate transcription factors that
produce growth-associated proteins. Neurite outgrowth is seen when these genes
are over-expressed. CNS neurons don’t express these genes in the same manner.3 Figure 3 highlights the importance of RAGs
and the myelin-associated inhibitors of Oligodendrocytes in axon
regeneration/lack of regeneration.

Figure 3 – differences
in molecular and cellular responses seen in the PNS and CNS following injury13


Along with this,
neurotrophins and cell-adhesion molecules are up-regulated following axotomy.7 Neurotrophins act as dimers that activate
downstream signalling pathways that activate RAGs, promoting survival.14 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 developed?

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.4 Studies have highlighted parallels between
mechanisms preventing axonal repair and those that limit experience-dependent
plasticity.15 Earlier it was mentioned the Nogo receptor
pathway inhibits axonal regeneration; the pathway also restricts adult neural
plasticity.16 It’s been observed that supressing nogo
receptor signalling enhances neural repair; it can be inferred neural repair
involves plasticity.17 Perhaps limited CNS regeneration is a price
to pay for higher intellectual capabilities.4


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.