Involvement of α7β1 integrin in the conditioning-lesion effect on sensory axon regeneration (original) (raw)
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Integrins promote axonal regeneration after injury of the nervous system
2018
Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system.
Journal of Neuroscience, 2008
Several different integrins participate in the complex interactions that promote repair of the peripheral nervous system. The role of the integrin ␣64 in peripheral nerve regeneration was investigated in mice by cre-mediated deletion of the Itgb4 (4) gene in Schwann cells. After a crush lesion of the sciatic nerve, the recovery of motor, but not that of sensory, nerve function in 4 ؊/؊ mice was delayed. Immunostaining of neurofilament-200 showed that there also is a significant reduction in the number of newly outgrowing nerve sprouts in 4 ؊/؊ mice. Morphometric quantitative measurements revealed that fewer axons are myelinated in the nonlesioned 4 ؊/؊ nerves. After a sciatic nerve crush lesion, 4 ؊/؊ mice did not only have fewer myelinated axons compared with lesioned wild-type nerve, but their axons also showed a higher g-ratio and a thinner myelin sheath, pointing at reduced myelination. This study revealed that the 4 protein remains expressed in the early stages of peripheral regeneration, albeit at levels lower than those before the lesion was inflicted, and showed that laminin deposition is not altered in the absence of 4. These results together demonstrate that integrin ␣64 plays an essential role in axonal regeneration and subsequent myelination.
Molecular and Cellular Neuroscience, 2003
Defects in laminins or laminin receptors are responsible for various neuromuscular disorders, including peripheral neuropathies. Interactions between Schwann cells and their basal lamina are fundamental to peripheral nerve development and successful myelination. Selected laminins are expressed in the endoneurium, and their receptors are developmentally regulated during peripheral nerve formation. Loss-of-function mutations have confirmed the importance and the role of some of these molecules. Here we show for the first time that another laminin receptor, ␣71 integrin, previously described only in neurons, is also expressed in Schwann cells. The expression of ␣7 appears postnatally, such that ␣71 is the last laminin receptor expressed by differentiating Schwann cells. Genetic inactivation of the ␣7 subunit in mice does not affect peripheral nerve formation or the expression of other laminin receptors. Of note, ␣71 is not necessary for basal lamina formation and myelination. Nonetheless, these data taken together with the previous demonstration of impaired axonal regrowth in ␣7-null mice suggest a possible Schwann cell-autonomous role for ␣7 in nerve regeneration.
9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration
Journal of Neuroscience, 2009
Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The ␣91 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the ␣9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of ␣9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling ␣9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express ␣9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in ␣9 integrinexpressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after ␣9 integrin treatment but remained elevated in control groups.
BMC Neuroscience, 2013
Background: In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4 +) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4 + neurons were isolated from dissociated DRG neurons, creating two groups-IB4 + and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. Results: The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4cells at t=0 (CTSH, Icam1, Itgβ1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4 + cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4 + cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4 + and IB4cells. However, both groups showed upregulation of Itgβ1 and Plaur after 24 hr on LN, the IB4 + group also had increased Plat, and the IB4cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both populations in relatively high levels but not detectably influenced by time in culture (Bsg, Cst3, Ctsb, Ctsd, Ctsl, Mmp14, Mmp19, Sparc. We carried out immunohistochemistry to confirm expression of proteins encoded by a number of these genes. Conclusions: Our results show that 1B4 + and IB4neurons differ in the expression of several genes that are associated with responsiveness to the ECM prior to culturing (AdamTs1, FN, Icam1, Lamb1, Plat, Plaur). The data suggest that the genes expressed at higher levels in the IB4neurons could contribute to the initial growth response of these cells in a permissive environment and could also represent a common injury response that subsequently promotes axon regeneration. The differential expression of several extracellular matrix molecules (FN, Lamb1, Icam) may suggest that the IB4neurons are capable of maintaining /secreting their local extracellular environment which could aid in the regenerative process. Overall, these data provide new information on potential targets that could be manipulated to enhance axonal regeneration in the mature nervous system.
Integrin-laminin interactions controlling neurite outgrowth from adult DRG neurons in vitro
Molecular and Cellular Neuroscience, 2008
A prerequisite for axon regeneration is the interaction between the growth cone and the extracellular matrix (ECM). Laminins are prominent constituents of ECM throughout the body, known to support axon growth in vitro and in vivo. The regenerative capacity of adult neurons is greatly diminished compared to embryonic or early postnatal neurons. Since most lesions in the nervous system occur in the adult, we have examined neurite outgrowth from adult mouse DRG neurons on four laminin isoforms (laminin-1/LM-111, laminin-2/LM-211, laminin-8/LM-411 and laminin-10/LM-511) in vitro. The growth on laminin-1 and -10 was trophic factor-independent and superior to the one on laminin-2 and -8, where growth was very poor in the absence of neurotrophins. Among other ECM proteins, laminins were by far the most active molecules. Using function-blocking antibodies to laminin-binding integrins, we identified non-overlapping functions of integrins alpha3beta1, alpha7beta1 and alpha6beta1 on different laminin isoforms, in that alpha3beta1 and alpha7beta1 integrins appeared to be specific receptors for both laminin-1 and-2, whereas integrin alpha6beta1 was a receptor for laminin-8 and-10. Lastly, by use of immunohistochemistry, expression of subunits of laminin-1, -2, -8 and -10 in sensory organs in the human epidermis could be demonstrated, supporting an important role for these laminins in relation to primary sensory axons.
International journal of molecular sciences, 2016
After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PL...
Facilitatory and inhibitory effects of glial cells and extracellular matrix in axonal regeneration
Current Opinion in Neurobiology, 1991
Recent studies have shown that Schwann ceils stimulate nerve regeneration by producing nerve growth factor in response to macrophage activation as well as by mediating growth through cell-surface and extracellular matrix adhesion molecules. Neurons sprouting in the central .' nervous system, however, encounter a hostile environment including mature oligodendrocytes with contact inhibitors of growth cone motility, * masses of proliferating astrocytes with surface properties that may block _ .:,,: ,,., regeneration, and an extracellular environment relatively rich in chondroitin ,* .; ' =,,_ ' sulfate and tenascin forming a matrix less permissive for regeneratiow;' ,, than that found in the peripheral nervous system. In addition, as neurons mature, integrins and cell adhesion molecules are reduced in number (transcriptionally) or in efficacy (post-translationally). Current Opinion in Neurobiology 1991, 1:407413 The effects of glial cells and extracellular matrix in axonal regeneration Carbonetto