sNerve regeneration in Wld mice is normalized by actinomycin (original) (raw)
Related papers
Neuroscience Letters, 1998
We have raised the hypothesis that differentiated Schwann cells repress regrowth of axons but become permissive upon dedifferentiation. Wld s mouse is a strain in which severed peripheral nerves do not degenerate for several weeks, and axonal regeneration does not occur either . In this strain, we studied the role of resident cells upon axonal regeneration by inhibiting transcription. Regeneration was assessed with the pinch test, electron microscopy and DiI (a fluorescent lipid soluble dye). After a crush, Wld s axons did not regenerate but they did so when the crush was made through a nerve segment treated with actinomycin D (ActD), an inhibitor of transcription. In contrast, when the crush was made distal to the treated segment no regeneration ensued. Our results support the notion that normal resident cells of peripheral nerves repress axonal growth.
Isolated axons of Wlds mice regrow centralward
Neuroscience Letters, 1999
We have conjectured that axons embody a post transcriptional sprouting programme repressed by mature Schwann cells. Injured nerves of Wld s mice neither degenerate nor regenerate for several weeks but axons do regrow if the resident cells of the distal stump are destroyed. To test our hypothesis we made an extended crush in Wld s nerves to destroy resident cells, transected the nerve at the proximal end of the lesion, and searched for sprouts in the injured domain. These isolated axons regrew centralward as supported by ultrastructure, labelling with horseradish peroxidase, and staining with Dil. This result indicates that: (i) axons embody a post transcriptional sprouting programme; (ii) resident cells of the nerve, probably Schwann cells, repress this programme, and (iii) navigation of regrowing axons is determined by the environment.
The cellular and molecular basis of peripheral nerve regeneration
Molecular Neurobiology, 1997
Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulinqike growth factors (IGFs), and glial-cell-linederived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neurop~.~tides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann ceils play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/ HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capaciPy of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regeneration may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair. Index Entries: Nerve regeneration; axotomy; neuronal death; Schwann cells; basal lamina; macrophages; growth-associated proteins; neuropoietic cytokines; neurotrophic factors; cell adhesion wtolecules. The abili~ of the peripheral nerve to regenerate and reirmervate denervated targets has been recognized for more than a century. However, complete functional recovery is rarely achieved, despite the considerable advances made in rnicrosurgical techniques and the *Author to whom all correspondence and reprint requests should be addressed.
The nerve regenerative microenvironment: Early behavior and partnership of axons and Schwann cells
Experimental Neurology, 2010
This review will address new ideas, including several from our laboratory, on the role of local molecules and signaling within the microenvironment of injured peripheral nerve trunks. These include the concepts of axon-Schwann cell (SC) outgrowth partnership such as the secretion of local molecules that may facilitate or inhibit regenerative activity and the role of directional cues secreted by the SCs to guide regrowing axons. Several specific themes along these lines are explored: (i) a role for peptidergic axon synthesis and signaling to SCs; (ii) the expression of molecular regeneration brakes in regenerating axons, specifically activated RHOA GTPase; (iii) the concept of misdirected axon outgrowth, focusing on the prototypic NGF and local TrkA interaction in adult regrowth; (iv) the role of extracellular basement membrane constituents such as laminin, RGD/fibronectin and their integrin receptors. We show that these different themes play an important but not exclusive role in determining regenerative success. Collectively, these individual findings help us appreciate the many facets of regenerative success which depend on the surrounding environment, the expressed receptors, and the internal state of the growing axon.
Rapid growth of regenerating axons across the segments of sciatic nerve devoid of schwann cells
Journal of Neuroscience Research, 1989
The characteristic response of Schwann cells (SC) accompanies peripheral nerve injury and regeneration. To elucidate their role, the question of whether or not regenerating axons can elongate across the segments of a peripheral nerve devoid of SC was investigated. Rat sciatic nerve was crushed so that the continuity of SC basal laminae was not interrupted. A segment about 15 mm long distal to the crush was either repeatedly frozedthawed to eliminate SC or scalded by moist heat which, in addition, denatured the proteins in the SC basal laminae, too. Both sensory and motor axons grew rapidly across the frozedthawed segment of the nerve. Their rate of elongation was reduced by only 30% in comparison to control crushed nerves. SC were not present along the path of growing axons adhering tightly to the bare SC basal laminae. The rate of elongation of regenerating sensory and motor axons in scalded nerve segments was eight times lower than in control crushed nerves. SC were present in that part of the scalded region that had been invaded by the regenerating axons but no further distally. These results suggest that acellular basal laminae of SC provide very good, although not optimal, conditions for elongation of regenerating sensory and motor axons. If biochemical integrity of the basal lamina is destroyed, the regenerating axons must be accompanied or preceded by viable SC, and axon elongation rate is significantly reduced.
Schwann cell mitosis in response to regenerating peripheral axons in vivo
Brain Research, 1985
Schwann cell mitosis has been demonstrated in chronically denervated cat tibial nerves re-innervated by axons regenerating from the proximal stump of a coapted peroneal nerve. Thymidine incorporation rose above baseline levels at the axon front, with no detectable increase in more distal regions occupied by denervated Schwann cells. Schwann cells therefore enter S phase upon the arrival of a regenerating axon in vivo as previously described in tissue culture. Intraneural treatment of the denervated distal stump with Mitomycin C prior to re-innervation delayed the subsequent appearance of myelin formation. This supports the notion that axonally snmulated division of Schwann cells is a prereqmsite for myelination during nerve regeneration. Axonal advancement was also retarded by drug treatment, possibly because of a reduced level of trophic support provided by the compromised Schwann cells. A comparable absence of myelin and poor re-innervation was found in chemically untreated distal stumps that had been maintained in the denervated state for prolonged periods when Schwann cell columns are known to undergo progressive atrophy. These observations suggest that nerve repair should be delayed for limited periods if efficacious regeneration is desired
Specificity of peripheral nerve regeneration: interactions at the axon level
2012
Peripheral nerves injuries result in paralysis, anesthesia and lack of autonomic control of the affected body areas. After injury, axons distal to the lesion are disconnected from the neuronal body and degenerate, leading to denervation of the peripheral organs. Wallerian degeneration creates a microenvironment distal to the injury site that supports axonal regrowth, while the neuron body changes in phenotype to promote axonal regeneration. The significance of axonal regeneration is to replace the degenerated distal nerve segment, and achieve reinnervation of target organs and restitution of their functions. However, axonal regeneration does not always allows for adequate functional recovery, so that after a peripheral nerve injury, patients do not recover normal motor control and fine sensibility. The lack of specificity of nerve regeneration, in terms of motor and sensory axons regrowth, pathfinding and target reinnervation, is one the main shortcomings for recovery. Key factors for successful axonal regeneration include the intrinsic changes that neurons suffer to switch their transmitter state to a pro-regenerative state and the environment that the axons find distal to the lesion site. The molecular mechanisms implicated in axonal regeneration and pathfinding after injury are complex, and take into account the cross-talk between axons and glial cells, neurotrophic factors, extracellular matrix molecules and their receptors. The aim of this review is to look at those interactions, trying to understand if some of these molecular factors are specific for motor and sensory neuron growth, and provide the basic knowledge for potential strategies to enhance and guide axonal regeneration and reinnervation of adequate target organs.
European Journal of Neuroscience, 2001
We have investigated the hypothesis that the chemorepellent Semaphorin3A may be involved in the failure of axonal regeneration after injury to the ascending dorsal columns of adult rats. Following transection of the thoracic dorsal columns, ®broblasts in the dorsolateral parts of the lesion site showed robust expression of Semaphorin3A mRNA. In addition, dorsal root ganglion (DRG) neurons with projections through the dorsal columns to the injury site persistently expressed both Semaphorin3A receptor components, neuropilin-1 and plexin-A1. These ascending DRG collaterals failed to invade scar regions occupied by Semaphorin3A-positive ®broblasts, even in animals which had received conditioning lesions of the sciatic nerve to enhance regeneration. Other axon populations in the dorsal spinal cord were similarly unable to penetrate Semaphorin3A-positive scar tissue. These data suggest that Semaphorin3A may create an exclusion zone for regenerating dorsal column ®bres and that enhancing the intrinsic regenerative response of DRG neurons has only limited effects on axonal regrowth. Tenascin-C and chondroitin sulphate proteoglycans were also detected at the injury site, which was largely devoid of central nervous system (CNS) myelin, showing that several classes of inhibitory factors, including semaphorins, with only partially overlapping spatial and temporal patterns of expression are in a position to participate in preventing regenerative axonal growth in the injured dorsal columns. Interestingly, conditioning nerve injuries enabled numerous ascending DRG axons to regrow across areas of strong tenascin-C and chondroitin sulphate proteoglycan expression, while areas containing Semaphorin3A and CNS myelin were selectively avoided by (pre)primed axonal sprouts.