Regulation of intrinsic neuronal properties for axon growth and regeneration

https://doi.org/10.1016/j.pneurobio.2006.12.001Get rights and content

Abstract

Regulation of neuritic growth is crucial for neural development, adaptation and repair. The intrinsic growth potential of nerve cells is determined by the activity of specific molecular sets, which sense environmental signals and sustain structural extension of neurites. The expression and function of these molecules are dynamically regulated by multiple mechanisms, which adjust the actual growth properties of each neuron population at different ontogenetic stages or in specific conditions. The neuronal potential for axon elongation and regeneration are restricted at the end of development by the concurrent action of several factors associated with the final maturation of neurons and of the surrounding tissue. In the adult, neuronal growth properties can be significantly modulated by injury, but they are also continuously tuned in everyday life to sustain physiological plasticity. Strict regulation of structural remodelling and neuritic elongation is thought to be required to maintain specific patterns of connectivity in the highly complex mammalian CNS. Accordingly, procedures that neutralize such mechanisms effectively boost axon growth in both intact and injured nervous system. Even in these conditions, however, aberrant connections are only formed in the presence of unusual external stimuli or experience. Therefore, growth regulatory mechanisms play an essentially permissive role by setting the responsiveness of neural circuits to environmental stimuli. The latter exert an instructive action and determine the actual shape of newly formed connections. In the light of this notion, efficient therapeutic interventions in the injured CNS should combine targeted manipulations of growth control mechanisms with task-specific training and rehabilitation paradigms.

Section snippets

Introduction—the relevance of growth control for neural function

Growth control is a crucial issue for any living organism. Growth processes determine size, form and structure of tissues and organs and, hence, shape their function (Conlon and Raff, 1999). Neural function depends on the number of nerve cells and on the quality, quantity and distribution of their connections. Contrary to many other tissues, however, the physiological properties of the nervous system must be continuously modified in response to the interaction with the surrounding world or the

Modes of axon growth

Axon growth is a complex phenomenon, which includes elongation of the stem neurite, sprouting and pruning of branches, formation or disconnection of synapses. All these processes are carried out according to two main modes of growth, termed elongating and arborising, which correspond to distinct degrees of activation of intrinsic neuronal mechanisms (Smith and Skene, 1997). Elongating mode (Fig. 1A) is the rapid, long-distance elongation of the main neuritic trunk towards its target, which

Intrinsic neuronal determinants of neuritic growth

In order to sustain neuritic growth a neuron has to synthesize structural components for the newly formed processes and to activate signal transduction pathways to sense and decode guidance cues. Such mechanisms depend on the level of expression of specific gene sets. It is generally assumed that this molecular machinery is fully active during elongating growth, either developmental or regenerative, whereas it is suppressed to some extent when the arborising mode is on (Skene, 1989, Skene, 1991

Developmental regulation of the intrinsic neuronal growth properties

The ability to activate growth genes and form growth cones substantially declines as neurons mature (Fawcett, 2001, Fernandes and Tetzlaff, 2001). At the same time, the capacity for sustaining extensive structural remodelling, which is characteristic of the juvenile brain, is also considerably reduced (Purves and Lichtman, 1985). Although this phase of development is associated with major changes in the overall properties of the nervous tissue microenvironment (Fawcett, 2001, Ferretti et al.,

Injury-derived regulation of intrinsic neuronal growth properties

Neural injury, and most notably axotomy, is a powerful stimulus that may lead to resume the elongating mode of neuritic growth. The neuronal response to injury is thus characterised by profound modifications of growth control that elicit de novo activation of specific genes and trigger structural remodelling. It is now well established that axon regeneration or compensatory plasticity in the adult are not a faithful recapitulation of developmental neuritogenesis or arbour formation, but involve

Procedures to enhance intrinsic growth potential

During the last few years different procedures have been developed to boost intrinsic neuronal growth properties. These strategies rely on three main methodological approaches, including conditioning lesions, pharmacological stimulation of the cell body response and overexpression of neuronal growth genes. Although the ultimate goal of these manipulations is to develop translatable therapeutic paradigms to promote regeneration, they also yield important insights on the functional interplay

How do enhanced intrinsic growth potentialities override environmental inhibition?

Numerous observations reported in the previous sections show that induction of neuronal growth genes allows neuritic elongation even in the presence of prohibitive external conditions (Fig. 4A–G). Surprisingly, however, little is known about the cellular/molecular interactions that enable neurons with enhanced growth potentialities to overcome extrinsic inhibition. Two possibilities may be envisaged. Activation of growth genes may simply shift the balance in favour of positive mechanisms,

Why do we need to control neuritic growth?

A salient feature of adult central neurons is the extreme variability of the intrinsic growth/regenerative potential among distinct populations. The reasons for such diverse features of CNS neurons are not known, but they are likely related to type- (or subtype-) specific functional tasks. For instance, in the inferior olive distinct neuron clusters, which correspond to anatomo-functional units in the cerebellar cortical network (Sotelo, 2004), show considerable differences in the constitutive

Acknowledgements

We are indebted to Drs Piergiorgio Strata and Annalisa Buffo for their valuable comments on the manuscript. Our work was supported by grants from International Institute for Research in Paraplegia (Zurich, P81/04); European Community (contract number 512039); Ministero dell’Università e della Ricerca Scientifica e Tecnologica (COFIN 2005), University of Turin, Regione Piemonte, Compagnia di San Paolo (Neurotransplant Project, no. 2004.2019).

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