Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration

Curinga, Gabrielle; Smith, George M.

doi:10.1016/j.expneurol.2007.06.026

Cited by 36 publications

(28 citation statements)

References 119 publications

(144 reference statements)

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“…In growth cones, however, the random exploration of the environment is coupled to a variety of feedback loops. These feedback loops are formed by: (i) the factors controlling axon growth and guidance molecules (Curinga and Smith, 2007); (ii) the receptors present on the growth cone membrane which detect these factors; (iii) the consequent activation of a signaling cascade within the growth cone. These loops are responsible for the rapid formation of physical contacts when two filopodia tips with appropriate receptors meet (see Fig.…”

Section: Computational Sectionmentioning

confidence: 99%

“…Growth cones contain a variety of adhesion molecules and receptors to guidance molecules (Bustamante et al, 2000;Yamagata et al, 2003;Huber et al, 2003;Curinga and Smith, 2007;Cline and Haas, 2008); a sophisticated intracellular biochemical machinery couples these receptors to the cytoskeleton (Gallo and Letourneau, 2000;Song and Poo, 2001;Gordon-Weeks, 2004) which is primarily composed of actin filaments and microtubules. Filopodia are usually composed of several bundles of actin filaments and occasionally of some microtubules (Howard, 2001, Schaefer et al, 2002.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanical computation in neurons

Laishram

Avossa

Shahapure

et al. 2009

Developmental Neurobiology

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Growth cones are the main motile structures located at the tip of neurites and are composed of a lamellipodium from which thin filopodia emerge. In this article, we analyzed the kinetics and dynamics of growth cones with the aim to understand two major issues: first, the strategy used by filopodia and lamellipodia during their exploration and navigation; second, what kind of mechanical problems neurons need to solve during their operation. In the developing nervous system and in the adult brain, neurons constantly need to solve mechanical problems. Growth cones must decide how to explore the environment and in which direction to grow; they also need to establish the appropriate contacts, to avoid obstacles and to determine how much force to exert. Here, we show that in sparse cultures, filopodia grow and retract following statistical patterns, nearly optimal for an efficient exploration of the environment. In a dense culture, filopodia exploration is still present although significantly reduced. Analysis on 1271, 6432, and 185 pairs of filopodia of DRG, PC12 and Hippocampal neurons respectively showed that the correlation coefficient |rho| of the growth of more than 50% of filopodia pairs was >0.15. From a computational point of view, filopodia and lamellipodia motion can be described by a random process in which errors are corrected by efficient feedback loops. This article argues that neurons not only process sensory signals, but also solve mechanical problems throughout their entire lifespan, from the early stages of embryogenesis to adulthood.

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Section: Computational Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanical computation in neurons

Laishram

Avossa

Shahapure

et al. 2009

Developmental Neurobiology

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“…In most experiments, neurotrophins need to be administered using a mini-pump to supply them for extended periods of time. Gene therapy not only supports long-term expression of neurotrophins, but also this expression can be directed to specific cells, regions, or within simple or complex gradients [104]. Another advantage is many viruses can be retrogradely transported, providing a mechanism for genetic transfer into the spinal cord with minimum trauma.…”

Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 99%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

Self Cite

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Summary: Motor, sensory, and autonomic functions can spontaneously return or recover to varying extents in both humans and animals, regardless of the traumatic spinal cord injury (SCI) level and whether it was complete or incomplete. In parallel, adverse and painful functions can appear. The underlying mechanisms for all of these diverse functional changes are summarized under the term plasticity. Our review will describe what is known regarding this phenomenon after traumatic SCI and focus on its relevance to motor and sensory recovery. Although it is still somewhat speculative, plasticity can be found throughout the neuraxis and includes various changes ranging from alterations in the properties of spared neuronal circuitries, intact or lesioned axon collateral sprouting, and synaptic rearrangements. Furthermore, we will discuss a selection of potential approaches for facilitating plasticity as possible SCI treatments. Because a mechanism underlying spontaneous plasticity and recovery might be motor activity and the related neuronal activity, activity-based therapies are being used and investigated both clinically and experimentally. Additional pharmacological and gene-delivery approaches, based on plasticity being dependent on the delicate balance between growth inhibition and promotion as well as the basic intrinsic growth ability of the neurons themselves, have been found to be effective alone and in combination with activitybased therapies. The positive results have to be tempered with the reality that not all plasticity is beneficial. Therefore, a tremendous number of questions still need to be addressed. Ultimately, answers to these questions will enhance plasticity's potential for improving the quality of life for persons with SCI.

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“…[1][2][3][4][5] However, functional regeneration rarely occurs in the CNS due to inhibition of axon growth and an absence of directed guidance (for review see Refs. 6,7 ). Cell-based therapies targeting damaged axonal pathways have shown promise on several fronts, including release of neuroprotective factors, local release of neurotransmitters at distal targets of lost pathways, and to provide myelinating cells to facilitate remyelination of denuded axons.…”

Section: Introductionmentioning

confidence: 99%

Microtissue Engineered Constructs with Living Axons for Targeted Nervous System Reconstruction

Cullen

Tang-Schomer

Struzyna

et al. 2012

Tissue Engineering Part A

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As a common feature of many neurological diseases and injury, the loss of axon pathways can have devastating effects on function. Here, we demonstrate a new strategy to restore damaged axon pathways using transplantable miniature constructs consisting of living neurons and axonal tracts internalized within hydrogel tubes. These hydrogel microconduits were developed through an iterative process to support neuronal survival and directed axon growth. The design included hollow agarose tubes providing a relatively stiff outer casing to direct constrained unidirectional outgrowth of axons through a central soft collagen matrix, with overall dimensions of 250 μm inner diameter ×500 μm outer diameter and extending up to several centimeters. The outer casing was also designed to provide structural support of neuronal/axonal cultures during transplantation of the construct. Using neuron culture conditions optimized for the microconduits, dissociated dorsal root ganglia neurons were seeded in the collagen at one end of the conduits. Over the following week, high-resolution confocal microscopy demonstrated that the neurons survived and the somata remained in a tight cluster at the original seeding site. In addition, robust outgrowth of axons from the neurons was found, with axon fascicles constrained in a longitudinal projection along the internal collagen canal and extending over 5 mm in length. Notably, this general geometry recapitulates the anatomy of axon tracts. As such, these constructs may be useful to repair damaged axon projections by providing a transplantable bridge of living axons. Moreover, the small size of the construct permits follow-on studies of minimally invasive transplantation into potentially sensitive regions of the nervous system.

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Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration

Cited by 36 publications

References 119 publications

Mechanical computation in neurons

Mechanical computation in neurons

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

Microtissue Engineered Constructs with Living Axons for Targeted Nervous System Reconstruction

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