The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system - PubMed (original) (raw)

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The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system

Bernhard K Mueller et al. Philos Trans R Soc Lond B Biol Sci. 2006.

Abstract

During the development of the nervous system, outgrowing axons often have to travel long distances to reach their target neurons. In this process, outgrowing neurites tipped with motile growth cones rely on guidance cues present in their local environment. These cues are detected by specific receptors expressed on growth cones and neurites and influence the trajectory of the growing fibres. Neurite growth, guidance, target innervation and synapse formation and maturation are the processes that occur predominantly but not exclusively during embryonic or early post-natal development in vertebrates. As a result, a functional neural network is established, which is usually remarkably stable. However, the stability of the neural network in higher vertebrates comes at an expensive price, i.e. the loss of any significant ability to regenerate injured or damaged neuronal connections in their central nervous system (CNS). Most importantly, neurite growth inhibitors prevent any regenerative growth of injured nerve fibres. Some of these inhibitors are associated with CNS myelin, others are found at the lesion site and in the scar tissue. Traumatic injuries in brain and spinal cord of mammals induce upregulation of embryonic inhibitory or repulsive guidance cues and their receptors on the neurites. An example for embryonic repulsive directional cues re-expressed at lesion sites in both the rat and human CNS is provided with repulsive guidance molecules, a new family of directional guidance cues.

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Figures

Figure 1

Figure 1

A retinal growth cone growing on a laminin substratum. Axon and growth cones are stained by the F-actin marker Alexa-phalloidin. Filopodia, lamellipodia and axonal protrusions (microspikes) are clearly visible.

Figure 2

Figure 2

Recombinant repulsive guidance molecule (RGM) is active in both stripe and collapse assays. (a) RGM-transfected membranes (left) but not control-transfected membranes (right) are repulsive for temporal retinal axons. (b) Supernatants from RGM-transfected cells (left) but not from mock-transfected cells (right) induce collapse of temporal retinal growth cones. RGM concentration used was 10 ng ml−1.

Figure 3

Figure 3

Amino acid sequences of repulsive guidance molecule (RGM) orthologues and homologues. (a) Amino acid sequence of human, rat and chick RGM A. (b) Amino acid sequence of human RGM A, B and C isoforms.

Figure 4

Figure 4

Schematic drawing of repulsive guidance molecule protein.

Figure 5

Figure 5

Schematic drawing of the repulsive guidance molecule receptor neogenin.

Figure 6

Figure 6

Repulsive guidance molecule (RGM) proteins are localized in fresh and mature lesion sites in injured human brain. In a patient dying from traumatic brain injury, after 12 h, (a) RGM-positive cells have already accumulated at the lesion site. The lesion is located in the right frontobasal part of the brain and the patient died from severe brain oedema. In older lesions, (b) scar tissue has formed at the injury site and extracellular RGM immunoreactivity is associated with fibrillar structures. This patient died 5 years after suffering a brain injury in the left and right frontobasal part of the brain and cause of death was pulmonary embolism.

Figure 7

Figure 7

The anti-repulsive guidance molecule (anti-RGM) A antibody, but not the IgG control antibody, promotes the regeneration of corticospinal tract axons after spinal cord injury. Camera lucida drawings of biotin-dextran-amine labelled corticospinal axons of a (a) control IgG-treated rat and an (b) anti-RGM A antibody-treated rat in consecutive parasagittal sections. Grey-coloured tissue corresponds to scar tissue at or adjacent to the transection injury lesion. Reproduced from the Journal of Cell Biology 2006; 173, 47–58 by copyright permission of the Rockefeller University Press.

Figure 8

Figure 8

The anti-repulsive guidance molecule (RGM) A antibody promotes functional recovery after spinal cord injury. The BBB score, a neurological rating score for evaluation of hind limb function, was determined at the indicated time points after dorsal hemisection injuries. RGM A antibody-treated animals (_n_=9) reached a final average BBB score of 15, control antibody-treated rats reached a score of 10.9 (_n_=11) and the sham-operated controls (_n_=5) reached a score like normal healthy rats of 21. The BBB scoring curves of control- and anti-RGM A-treated animals started to diverge five weeks post-injury, with the difference increasing further at later time points. Antibody treatment was done within the first two weeks post-injury (total dose: 80 μg per rat), starting immediately after injury. Reproduced from the Journal of Cell Biology 2006; 173, 47–58 by copyright permission of the Rockefeller University Press.

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