Certain biological mechanisms
differ between the nervous systems and this is what leads to different
regeneration capabilities between the systems. When PNS neurons are cut,
Regeneration Associated Genes (RAGs) that get activated. The upregulation of
these genes promotes axon regrowth after injury, whether in CNS or PNS.
Examples of such genes would be ATF3, Sox11, GAP-43 and c-Jun. In contrast, RAGs
do not get upregulated as much in the CNS as PNS and this is a key difference
because it tells us that even if inhibitors were not present within the CNS,
there would be limited axon regeneration (Huebner et al, 2009).
from the lack of RAG upregulation, there are 2 key classes of CNS regeneration
inhibitors; Myelin- Associated Inhibitors (MAIs) and Chondroitin Sulfate
Proteoglycans (CSPGs). MAIs are expressed by oligodendrocytes as part of the
CNS myelin. Nogo-A, OMgp, Sema4D and MAG are all examples of MAIs. Even though
all of these molecules are structurally different from one another, they all
bind to a particular receptor in order to inhibit axon regrowth; NgR1. This
NgR1 receptor does not have a cytoplasmic/ transmembrane domain. It interacts
with LINGO-1, TAJ/TROY coreceptors. Apart from MAG, all of the other MAIs are
exclusive found within CNS myelin.
discovery of NoGo provides supporting evidence for its role in inhibiting axon
regeneration. Martin Schwab (2000) showed that if CNS neurones are grown in tissue
culture made of Schwann cells substrates, axons will grow but if the tissue
culture is made of Oligodendrocyte substrates, then axons do not extend
outwards. This therefore meant that there must be some glial factor that is
either present or absent in CNS glia that inhibits axon regrowth. Further research
lead to NoGo becoming discovered. Nogo is released when oligodendrocytes are damaged,
only made in mammalian oligodendrocytes, and presence inhibits axon regrowth in
a CNS environment. To overcome this suppression of axon growth by NoGo,
antibodies were raised against Nogo. These antibodies were injected into adult
rats following injury to the spinal cord and about 5% of the damages axons
regenerated back. Although 5% does not seem like a significant amount, it still
allowed the animal to be able to function at a good enough level.(Bear, Connors
and Paradiso, 2006). This proves that molecules like NoGo are primarily
responsible for the lack of regeneration in CNS.
other class of inhibitors in CNS regeneration are CSPGs. Examples of CPSGs
include neurocan, versican, brevican and phosphacan. These molecules are often
found membrane bound or in the extracellular space and their production is
increased by reactive astrocytes when there has been damage to CNS. CSPGs are
the main molecules found in astroglial scar. Since this glial scar is a major
opponent to CNS regeneration, obstructing CSPG activity can allow axon
regeneration to occur in the CNS (Huebner et al, 2009).
Since debris are cleared much faster in the
PNS than CNS, MAGS present in PNS myelin are cleared out before it can have an
impact (Huebner et al, 2009). This is what leads to almost complete axon
regeneration in the PNS because Scavenger cells of the immune system clear those
cellular debris. This in turn encourages the Schwann cells to produce and
release growth factors. Once the regenerated neuron has built new processes to
contact the neighbouring neurons, the scavenger cells go back to resting state.
Schwann cells remyelinate the newly formed processes and old rescue processes (Jochen Müller,2013). Regeneration within the PNS is successfully
are also other molecules that inhibit axon regeneration within the CNS. These molecules aren’t present in the
astroglial scar. Axon- Regeneration Inhibitors (AREs) such as RGM and semaphorin
3A activate a small GTPase gene called RhoA. Activation of this gene leads to
the subsequent activation of an associated protein kinase 2 called ROCK2. ROCK2
activation causes neural regeneration to stop. As a result, by blocking ROCK2
or RhoA activity, CNS axon regeneration can be promoted (Huebner et al, 2009).
back to the earlier point, it is the different environments that decide whether
axons can regrow or not. For example, a
dorsal root ganglion axon of the PNS can regenerate in the peripheral nerve but
the moment it hits the dorsal horn – which is CNS environment- the axon’s growth stops. Similarly, an alpha
motor neurone of the CNS can regrow if it gets cut in the peripheral nerve –
i.e. PNS environment- but it cannot grow back to its target had it been cut in
the CNS (Bear, Connors and Paradiso, 2006). This reinforces the importance of
environment in regenerative potential.
structure is the CNS-PNS transitional zone (TZ). TZ is a rootlet that has both
central and peripheral tissues. These tissues are kept separate by astrocytic
tissue that has myelin sheaths in the centre, made by oligodendrocytes. The
periphery of this astrocytic tissue is made of Schwann cells. This
translational zone can only be accessed by axons (J.P.Fraher, 2000). By studying rat dorsal root TZs from the
spinal cord tissue, J.P. Fraher et al found that the CNS part of this
transitional zone responds to axon degeneration and regeneration in a way which
corresponds to the response that would occur in the CNS after an injury. This
is because gliosis takes place, which is the CNS response to damage whereby CNS
glia) becomes hypertrophic or increase in number. Since this only occurs in the
CNS part of the TZ, it shows that there is a clear distinction between how the
two nervous systems are characterised.