Neurite-myelin interaction in the control of purkinje axon growth and regeneration.
The limited regenerative capability of adult central neurons results from an interplay between the intrinsic growth potential of injured nerve cells and environmental growth-inhibitory signals, such as myelin-associated molecules. These molecules, which are known to inhibit axonal regeneration, are expressed in the adult intact central nervous system, suggesting that they also exert a constitutive regulatory function on uninjured neurites. However, most of the mechanisms underlying this function of myelin-associated factors are still unclear. To address this issue, we examined Purkinje cells, which show extremely poor regenerative capabilities. Such a weak intrinsic growth potential is attributed, at least in part, to inhibitory activity exerted by the myelin-associated molecule Nogo-A on growth-associated gene expression and axon plasticity of adult Purkinje cells. Indeed, the regenerative potential of these neurons declines during postnatal development in parallel with myelin deposition. In addition, myelin-associated factors regulate the development of the Purkinje axon intracortical plexus, contributing to the shaping of mature cerebellar connectivity. The action of environmental inhibitory factors can be partially counteracted by overexpression of neuronal growth-associated molecules. In fact, following axotomy, transgenic Purkinje cells that overexpress GAP-43 are able to sprout their axons into white matter and show a pronounced tendency to lose myelin. Altogether, these results suggest that the control exerted by myelin on Purkinje axon plasticity plays an important role in preventing aberrant growth and in stabilizing intracortical connectivity. Such a constitutive regulation may eventually hamper compensatory mechanisms set up by the same neurons in response to injury and thus determine their weak regenerative abilities.
Gianola
Sara
S
Rita Levi Montalcini Centre for Brain Repair, Department of Neuroscience, University of Turin, Italy. sara.gianola@unito.it
Rossi
Ferdinando
F
D000818:Animals; D001369:Axons / Q000378:metabolism*; D002525:Cerebellar Cortex / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism*