When the RAGs do not get upregulated as
When PNS neurons are cut, Regeneration Associated Genes (RAGs)
that promote axon regrowth get activated. Examples of such genes would be ATF3,
Sox11, GAP-43 and c-Jun. In the CNS, the RAGs do not get upregulated as much.
There are instead inhibitory molecules present in the CNS that create an
obstacle for axon regeneration. This is a key difference because such kind of
upregulation does not happen in the CNS. So, even if inhibitors were not
present within the CNS, there would be limited axon regeneration (Huebner et
Apart 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 oligodendroglia as part of
the CNS myelin. Nogo-A, Omgp, Sema4D and MAG are all examples of MAIs. Although
all of these molecules are structurally different from one another, they all
bind to the receptor NgR1 in order to inhibit axon regrowth. This NgR1 receptor
does not have a cytoplasmic/ transmembrane domain. In order to inhibit axon
regeneration, it interacts with LINGO-1, TAJ/TROY coreceptors. Apart from MAG,
all of the other MAIs are exclusive to CNS myelin. Since PNS debris are cleared
much faster than CNS debris, MAG being present in PNS myelin is 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 the quick removal of debris by Scavenger cells encourages
regeneration by participation of the Schwann cells as growth factors are
released by the Schwann cells. Once the regenerated neuron has built new
processes to contact the neighbouring neurons, the scavenger cells go back to
resting state. The Schwann cells remyelinate the newly formed and old rescue
processes (Jochen Müller,2013).
The other class of
inhibitors in CNS regeneration are CSPGs. These are the main molecules found in
astroglial scar. This glial scar is a major opponent to CNS regeneration since
it isolates the injury site and blocks neurons from trying to regenerate axon.
Examples of CPSGs include neurocan, versican, brevican and phosphacan. The
production of CSPGs, often found bound to the membrane or in extracellular space,
is increased by reactive astrocytes when there has been damage to CNS (Huebner
et al, 2009).
There are also other molecules that inhibit axon regeneration
within the CNS. Axon- Regeneration Inhibitors (AREs) such as RGM and semphorin
3A activate a small GTPase gene called RhoA. Activation of this gene leads to
the activation of an associated protein kinase 2 called ROCK2. This activation
causes neural regeneration to cease.
Experimental evidence by Schwab showed that if CNS neurones are
grown in tissue culture that has substrates made of Schwann cells, then axons
will grow but if the tissue culture is made of Oligodendrocytes substrates, then
axons do not extend outwards. Therefore, this meant that there must be some
glial factor that is either present or absent in CNS glia that inhibits axon
regrowth. Further research led to a molecule called Nogo to be discovered. Nogo
is released when oligodendroglia are damaged and it therefore inhibts axon regrowth in a CNS
environment. It is only made in the oligodendrocytes and only in mammals. Fish
do not make Nogo (Bear, Connors and Paradiso, 2006, p705).
To over come 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.
Referring 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. (Neuroscience book, p705)
This tells us that the peripheral nerve holds a key
characteristic that allow axons to regrow after injury. This characteristic is
the myelinating glial cell, Schwann cell in PNS and Oligodendrocytes in the
An interesting structure is the CNS-PNS transitional zone (TZ). TZ
is a rootlet that has both central and peripheral nervous properties. The central
and peripheral 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 (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 ( microglia, astrocytes and
oligodendrocytes) becomes hypertrophic or increase in number.
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.