What in tubes known as Bünger bands and express

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 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

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 begin 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



After the distal
stump (PNS) shows Wallerian degeneration, axonal sprouts from the proximal
segment will enter the distal portion of the neuron and and reaches its target
after growing along the nerve. Schwann cells attract 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 in a distal
manner 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, reactive astrocytes  upregulate CSPGs after CNS injury.4 A
review of CSPGs demonstrated that after CNS injury, CSPG expression was
increased,  indicating the non-permissive
nature of glial scarring is partly attributed to the increased expression of
CSPGs.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 demonstrating the non-permissive role
CSPGs play 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. Neurite outgrowth is observed when these
genes are over-expressed. 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 regeneration.

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 the similarities in the mechanisms
prevenring 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. 


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