Certain oligodendrocytes are damaged, only made in

 Certain biological mechanismsdiffer between the nervous systems and this is what leads to differentregeneration capabilities between the systems. When PNS neurons are cut,Regeneration Associated Genes (RAGs) that get activated. The upregulation ofthese 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, RAGsdo not get upregulated as much in the CNS as PNS and this is a key differencebecause it tells us that even if inhibitors were not present within the CNS,there would be limited axon regeneration (Huebner et al, 2009).  Apartfrom the lack of RAG upregulation, there are 2 key classes of CNS regenerationinhibitors; Myelin- Associated Inhibitors (MAIs) and Chondroitin SulfateProteoglycans (CSPGs). MAIs are expressed by oligodendrocytes as part of theCNS myelin.

Nogo-A, OMgp, Sema4D and MAG are all examples of MAIs. Even thoughall of these molecules are structurally different from one another, they allbind to a particular receptor in order to inhibit axon regrowth; NgR1. ThisNgR1 receptor does not have a cytoplasmic/ transmembrane domain. It interactswith LINGO-1, TAJ/TROY coreceptors. Apart from MAG, all of the other MAIs areexclusive found within CNS myelin.Thediscovery of NoGo provides supporting evidence for its role in inhibiting axonregeneration. Martin Schwab (2000) showed that if CNS neurones are grown in tissueculture made of Schwann cells substrates, axons will grow but if the tissueculture is made of Oligodendrocyte substrates, then axons do not extendoutwards. This therefore meant that there must be some glial factor that iseither present or absent in CNS glia that inhibits axon regrowth.

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Further researchlead to NoGo becoming discovered. Nogo is released when oligodendrocytes are damaged,only made in mammalian oligodendrocytes, and presence inhibits axon regrowth ina CNS environment. To overcome this suppression of axon growth by NoGo,antibodies were raised against Nogo. These antibodies were injected into adultrats following injury to the spinal cord and about 5% of the damages axonsregenerated back.

Although 5% does not seem like a significant amount, it stillallowed the animal to be able to function at a good enough level.(Bear, Connorsand Paradiso, 2006). This proves that molecules like NoGo are primarilyresponsible for the lack of regeneration in CNS.Theother class of inhibitors in CNS regeneration are CSPGs.

Examples of CPSGsinclude neurocan, versican, brevican and phosphacan. These molecules are oftenfound membrane bound or in the extracellular space and their production isincreased by reactive astrocytes when there has been damage to CNS. CSPGs arethe main molecules found in astroglial scar. Since this glial scar is a majoropponent to CNS regeneration, obstructing CSPG activity can allow axonregeneration to occur in the CNS (Huebner et al, 2009).

 Since debris are cleared much faster in thePNS than CNS, MAGS present in PNS myelin are cleared out before it can have animpact (Huebner et al, 2009). This is what leads to almost complete axonregeneration in the PNS because Scavenger cells of the immune system clear thosecellular debris. This in turn encourages the Schwann cells to produce andrelease growth factors. Once the regenerated neuron has built new processes tocontact 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 successfullycompleted. Thereare also other molecules that inhibit axon regeneration within the CNS.  These molecules aren’t present in theastroglial scar.

Axon- Regeneration Inhibitors (AREs) such as RGM and semaphorin3A activate a small GTPase gene called RhoA. Activation of this gene leads tothe subsequent activation of an associated protein kinase 2 called ROCK2. ROCK2activation causes neural regeneration to stop. As a result, by blocking ROCK2or RhoA activity, CNS axon regeneration can be promoted (Huebner et al, 2009).Referringback to the earlier point, it is the different environments that decide whetheraxons can regrow or not.  For example, adorsal root ganglion axon of the PNS can regenerate in the peripheral nerve butthe moment it hits the dorsal horn – which is CNS environment-  the axon’s growth stops. Similarly, an alphamotor 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 inthe CNS (Bear, Connors and Paradiso, 2006). This reinforces the importance ofenvironment in regenerative potential.An interestingstructure is the CNS-PNS transitional zone (TZ).

TZ is a rootlet that has bothcentral and peripheral tissues. These tissues are kept separate by astrocytictissue that has myelin sheaths in the centre, made by oligodendrocytes. Theperiphery of this astrocytic tissue is made of Schwann cells.

Thistranslational zone can only be accessed by axons (J.P.Fraher, 2000).  By studying rat dorsal root TZs from thespinal cord tissue, J.P. Fraher et al found that the CNS part of thistransitional zone responds to axon degeneration and regeneration in a way whichcorresponds to the response that would occur in the CNS after an injury. Thisis because gliosis takes place, which is the CNS response to damage whereby CNSglia) becomes hypertrophic or increase in number. Since this only occurs in theCNS part of the TZ, it shows that there is a clear distinction between how thetwo nervous systems are characterised.