Regulation of intrinsic neuronal properties for axon growth and regeneration
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).
References (374)
- et al.
Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice
Cell
(1995) - et al.
Effect on the rat hypoglossal nucleus of vinblastine and colchicine applied to the intact or transected hypoglossal nerve
Exp. Neurol.
(1988) - et al.
Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype. With a critique of slow transport theory
Prog. Neurobiol.
(2000) - et al.
The neurite-promoting effect of laminin is mediated by different mechanisms in embryonic and adult regenerating mouse optic axons in vitro
Dev. Biol.
(1997) - et al.
Expression of polysialylated NCAM but not L1 or N-Cadherin by regenerating adult mouse optic fibers in vitro
Exp. Neurol.
(1999) - et al.
Axon outgrowth is regulated by an intracellular purine-sensitive mechanism in retinal ganglion cells
J. Biol. Chem.
(1998) Dependence of GAP-43 (B50, F1) transport on axonal regeneration in rat dorsal root ganglion neurons
Brain Res.
(1988)- et al.
Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target
Cell
(2002) - et al.
Electrical stimulation restores the specificity of sensory axon regeneration
Exp. Neurol.
(2005) - et al.
Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets
Neuroscience
(1998)
Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth in vitro
Neuron
Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation
Neuron
Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones
Neuron
Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex
Exp. Neurol.
Reparative mechanisms in the cerebellar cortex
Prog. Neurobiol.
Regeneration of the adult central nervous system
Curr. Biol.
Nervous system reorganization following injury
Neuroscience
Calcium influx is necessary for optimal regrowth of transacted neurites of rat sympathetic ganglion neurons in vitro
Neuroscience
Size control in animal development
Cell
What is the signal for chromatolysis?
Brain Res.
Injury-induced class 3 Semaphorin expression in the rat spinal cord
Exp. Neurol.
Failure to form a stable topographic map during optic nerve regeneration: abnormal activity-dependent mechanisms
Exp. Neurol.
Cell death and axon regeneration of Purkinje cells after axotomy: challenges of classical hypotheses of axon regeneration
Brain Res. Rev.
Development of the cerebellar cortical efferent projection: an in vitro study in rat brain slices
Dev. Brain Res.
Electrical stimulation accelerates and enhances expression of regeneration-associated genes in regenerating rat femoral motoneurons
Cell. Mol. Neurobiol.
Retinal ganglion cell axons recognize specific guidance cues present in the deafferented adult rat superior colliculus
J. Neurosci.
Recognition of specific targets by cultured dorsal root ganglion neurons
J. Neurosci.
Proteoglycans in the developing brain; new conceptual insights for old proteins
Physiol. Rev.
Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys
Exp. Brain Res.
Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord
J. Neurosci.
The injured spinal cord spontaneously forms a new intraspinal circuit in the adult rat
Nat. Neurosci.
Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury
J. Neurosci.
Sorting of beta-actin mRNA and protein to neurites and growth cones in culture
J. Neurosci.
Optic nerve regenerates but does not restore topographic projections in the lizard Ctenophorus ornatus
J. Comp. Neurol.
Training on a visual task improves the outcome of optic nerve regeneration
J. Neurotrauma
Expression of GAP-43 in the granule cells of rat hippocampus after seizure-induced sprouting of mossy fibres: in situ hybridization and immunocytochemical studies
Eur. J. Neurosci.
Transported proteins in the regenerating optic nerve: regulation by interaction with the optic tectum
Science
Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury
Proc. Natl. Acad. Sci. U.S.A.
Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth
Proc. Natl. Acad. Sci. U.S.A.
Alterations in membrane potential after axotomy at different distances from the soma of an identified neuron and the effect of depolarization on neurite outgrowth and calcium channel expression
J. Neurophysiol.
Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve
J. Neurocytol.
Cyclic AMP-induced repair of zebrafish spinal circuits
Science
Nucleus hears axon's pain
Nat. Med.
Neuroprotective fibroblast growth factor type-2 down-regulates the c-Jun transcription factor in axotomized sympathetic preganglionic neurons of adult rat
Neuroscience
Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons
Nat. Neurosci.
Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth
J. Neurosci.
Target contact regulates GAP-43 and alpha-tubulin mRNA levels in regenerating retinal ganglion cells
J. Neurosci. Res.
Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injury-dependent and reactivated developmental processes
J. Neurochem.
The developmental loss of the ability of Purkinje cells to regenerate their axons occurs in the absence of myelin: an in vitro model to prevent myelination
J. Neurosci.
Spinal cord repair strategies: why do they work?
Nat. Rev. Neurosci.
Cited by (130)
Spatial confinement: A spur for axonal growth
2023, Seminars in Cell and Developmental BiologyB23/Nucleophosmin promotes reconstitution of synaptic path in hippocampus after injury
2019, Biochemical and Biophysical Research CommunicationsThe Intrinsic Role of Epigenetics in Axonal Regeneration
2019, Epigenetics and RegenerationThe C. elegans BRCA2-ALP/Enigma Complex Regulates Axon Regeneration via a Rho GTPase-ROCK-MLC Phosphorylation Pathway
2018, Cell ReportsCitation Excerpt :The success of axon regeneration is highly variable and is governed by the interplay between its intrinsic growth capacity and the local extracellular environment (Rossi et al., 2007). Axon regeneration in the injured neuron involves multiple intracellular processes such as cytoskeletal rearrangements and growth cone formation (Rossi et al., 2007). Although intrinsic regenerative signals can affect the success of regeneration, the specific signaling pathways by which axons regenerate following injury have yet to be fully elucidated.