Part II: The difference between centre and periphery

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Cells of the peripheral (PNS) and central nervous system (CNS) clearly differ in their ability to regenerate. Neurons in the PNS show a remarkable ability to heal, while in the CNS  few spontaneous regeneration occurs. In order to shed light on the underlying mechanisms we focused in part one on the environmental influence, like growth-inhibitory substances from support cells. In this part we will concentrate on the genetic prerequisites of neurons to react on signals from the environment, may they be inhibitory or stimulatory.

What's the problem?

All cells in an organism share the identical genetic information. But obviously this alone does not define a cell, since they appear in numerous shape and function. The difference lies in the cells’ specific use of this genetic information. The activity of genes, or their ability to be activated, is a critical factor and ultimately responsible for the shape a cell is going to have, which tasks it is going to perform and how it will react to its environment. In this context, a neuron of the CNS, would not regrow even in an environment promoting growth if its regeneration genes are inactive.

The devil is in the details

The nervous system of an organism is created during development. Neurons grow along tracks of molecular guideposts towards the right position. Upon embryonic to adult transition the neurons lose their ability to grow. This loss protects the system from forfeiting important connections once the numerous paths have been properly generated. To accomplish this, the intrinsic neuronal growth ability is repressed in favour of proper synaptic development. Genes required for growth are inactivated or down regulated in activity and the transport machinery for cellular material along the process is reduced. This inactivation and repression has to be neutralised to allow for regeneration after injury.

The basic problem

There are several preconditions for regeneration of a severed neuronal process. First of all, in order to successfully respond to injury, damage to the process must be detected by the cell body, because the answer to the injury is directed from the genetic material in the nucleus lying in the cell body. The information about the injury has to be transported from the site of injury through the process, which can be of considerable length, to the cell body and into the nucleus. In order to understand the relative distances to be dealt with, if the cell body of a neuron had the size of a tennis ball, its axon would have a length of several kilometres.

Genes located in the nucleus have to be released of inactivation, then read and afterwards proteins have to be synthesized. These have then to be transported back to the growing tip of the process. It was shown that nearly all of the mentioned events are incomplete or fail altogether in the injured CNS.

The journey is the reward

Signalling molecules can be transported from the tip of a process back to the cell body by means of cellular machinery, working much like a bucket brigade. It is assumed that neuronal populations signal damage with different efficacy. This could be a reason for the reduced ability of central neurons to regenerate.

The cells are the difference

Peripheral neurons upregulate the activity of genes associated with regeneration after injury. Some of these genes play a direct role in the regeneration, whereas others do not. However, central neurons do not up regulate genes associated with regeneration to the same extent as peripheral neurons do. In contrast to the PNS, upregulation of genes is relatively low in the CNS after injury. Therefore, the neurons themselves are pivotal factors for a lack of regeneration in the CNS.

Border crossers

There are cells in the nervous system showing these differences quite clearly. The so-called dorsal root ganglion cells are unique in a way as they belong to the periphery and to the CNS at the same time. They indeed have an axon part that projects to the periphery and one that projects to the CNS. Injury of the peripheral process lead to an up regulation of genes associated with regeneration, resulting in its regrowth. However, if the central process is injured the regenerative response is not nearly as robust and the central process is unable to regenerate.

On the other hand dorsal root ganglion cells can be trained. It has been shown that regeneration of the CNS branch of these neurons could be enhanced by a prior injury to the peripheral branch. The cell "learned" to regenerate in consequence of this so-called "conditioning lesion". It augmented the growth status of the neuron so that also the central branch is enabled to regenerate in the growth-unfriendly environment of the CNS. Signalling molecules affecting the neuronal growth status seem to be responsible for that. It could be shown that the concentration of these molecules is elevated after a conditioning lesion. This leads to a signalling cascade ending in the activation and transcription of several growth-associated genes.

The consequence: it's in the mix

There is a fine balance of environmental signals and the ability of a cell to react to it. In sum, it is this balance, a mixture of gene activity and environmental factors, which determines the chances to cure spinal cord injury. For science this means that a prerequisite for modifying this complex system is the knowledge of intrinsic mechanisms (genes and cellular machinery) as well as extrinsic mechanisms (cellular environment). In the end it is a combination of different approaches that promises success.

Text: Jochen Müller, Rosi Lederer, Verena May
Graphics: Vieri Failli