RETROGRADE AXONAL TRANSPORT OF RAPIDLY MIGRATING LABELLED PROTEINS AND GLYCOPROTEINS IN REGENERATING PERIPHERAL NERVES

Abstract— The redistribution of rapidly migrating [³H]leucine-labelled proteins and [³H]fucose-labelled glycoproteins was studied in ligated regenerating hypoglossal and vagus nerves of the rabbit. When regenerating and contralateral hypoglossal nerves were ligated 16 h after labelling of the nerve cell bodies, rapidly migrating proteins and glycoproteins accumulated distal to the ligatures indicating a rapid retrograde transport from the peripheral parts of the nerves within 6 h. The retrograde accumulation of both proteins and glycoproteins was greater on the regenerating side than on the contralateral side at both 1 and 5 weeks after a nerve crush. Labelled proteins and glycoproteins also accumulated proximal to the ligatures, indicating a delayed rapid anterograde phase of axonal transport. The accumulation of this phase was also greater on the regenerating side 1 week after a nerve crush for both labelled proteins and glycoproteins. One week after a crush of the cervical vagus nerve, rapidly migrating proteins and glycoproteins redistributed between he crush zone and a proximal ligature applied 16 h after labelling of the nerve cell bodies. A retrograde accumulation occurred distal to the ligature within 6 h, indicating a rapid retrograde transport from the crush zone.     

Tyrosination State of α-Tubulin in Regenerating Peripheral Nerve

Abstract: Certain modifications of the neuronal cytoskeleton that are associated with development also occur during regeneration of adult mammalian peripheral nerve. The aim of the present study was to examine one such modification, the tyrosination of a-tubulin. Adult rats were anaesthetized and the left or right sciatic nerve randomly selected and crushed to induce regeneration. In certain instances nerves were crushed then ligatured about the crush, to prevent regeneration. Five days later the rats were killed and the regenerating (or ligatured) and the contralateral (control) nerves were removed. Quantitative immunoblotting of nerve homogenates with antibodies that recognize tyrosinated a-tubulin and total a-tubulin revealed a significant increase (p < 0.01) in the proportion of a-tubulin that was tyrosinated in nerve pieces distal (peripheral) to a nerve crush compared with nerve pieces proximal (central) to a nerve crush and to uncrushed nerve. No such difference occurred in ligatured (crushed but nonregenerating) nerve, implying that the increase was related to the presence of regenerating fibres; nor was there any gradient in tyrosination of α-tubulin in control nerves. This effect was confirmed by cytofluorimetric scanning and fluorescence confocal laser scanning microscopy of fixed sections of control and regenerating nerve, stained with antibodies directed against tyrosinated a-tubulin. When nerves were separated into fractions containing assembled and nonassembled tubulin, a significant (p < 0.01) increase was found in the proportion of tyrosinated α-tubulin in the nonassembled tubulin fraction in nerve pieces containing regenerating fibres. This occurred in the absence of a change in the proportion of assembled and nonassembled tubulin. Measurements of tubulin:tyrosine ligase activity, by incorporation of [³H] tyrosine into endogenous nerve tubulin in vitro, indicated a decrease in tyrosine incorporation into tubulin from nerve pieces distal, compared with those proximal to a nerve crush. There was no such difference in ligatured nerves. It is proposed that the increased amount of tyrosinated a-tubulin is related to an alteration in assembly rate of microtubules required for neurite outgrowth and that the apparent decrease in the tubulin:tyrosine ligase activity in vitro reflects the increased tyrosination in vivo.     

A role for Nogo receptor in macrophage clearance from injured peripheral nerve

We report a role for Nogo receptors (NgRs) in macrophage efflux from sites of inflammation in peripheral nerve. Increasing numbers of macrophages in crushed rat sciatic nerves express NgR1 and NgR2 on the cell surface in the first week after injury. These macrophages show reduced binding to myelin and MAG in vitro, which is reversed by NgR siRNA knockdown and by inhibiting Rho-associated kinase. Fourteen days after sciatic nerve crush, regenerating nerves with newly synthesized myelin have fewer macrophages than cut/ligated nerves that lack axons and myelin. Almost all macrophages in the cut/ligated nerves lie within the Schwann cell basal lamina, while in the crushed regenerating nerves the majority migrate out. Furthermore, crush-injured nerves of NgR1- and MAG-deficient mice and Y-27632-treated rats show impaired macrophage efflux from Schwann cell basal lamina containing myelinated axons. These data have implications for the resolution of inflammation in peripheral nerve and CNS pathologies.     

The peripheral and central changes resulting from cutting or crushing the afferent nerve supply to the whiskers

In neonatal rats, crushing or cutting the infraorbital nerve, the sensory nerve supply to the whiskers, has been found to prevent cortical barrel formation. However, both procedures are followed by regeneration of one-third to one-half of the nerve fibres and reinnervation of the whiskers. By counting fibres in individual whisker follicle nerves, it has been shown that 29-67% (mean 45%) of the myelinated fibres regenerate to the whiskers after a crush compared to 24-56% (mean 39%) after a cut. Further differences between the crush and cut lesions were indicated by studies on the time course of regeneration. Counts of the regenerating fibres at various ages as well as recordings of cortical evoked potentials in normal, nerve-crushed and nerve-cut animals showed that recovery was 3-4 days earlier in the nerve-crushed, compared with the nerve-cut animals. In normal and nerve-crushed animals the evoked potential was first detectable 2-3 days after birth while the response after nerve cut could not be recorded until day 7. Even after 60 days the amplitude of responses on both crushed and cut pathways was only about one-third of normal, while the latency was prolonged (normal 5.8 +/- 0.25 ms, crush 6.5 +/- 0.26 ms, cut 7.7 +/- 0.67 ms). Central changes occurring as a result of nerve cut or crush have been studied by microelectrode recordings from the trigeminal nucleus (the first synaptic level) and the somatosensory cortex. These also indicate clearly the greater severity of the cut lesion. Thus, in crushed animals, all levels of the trigeminal nucleus as well as the cortex show only minor modifications. The whiskers occupy the same total area and responses from all whiskers are present at their normal sites. However, after nerve cut, the responses from both the trigeminal nucleus and cortex show clear abnormalities. The total whisker area is reduced with a concomitant expansion of responses from the nose, check, lower jaw, and whiskers by the eye and ear. In addition, only one-third to one-half of the whiskers give responses. The site of these abnormalities is localized to the trigeminal nucleus since all whiskers show innervation in the peripheral nerve. It is suggested that the longer recovery time as well as the reduced accuracy of reinnervation may contribute to the poorer central recovery after a nerve cut.     

Regeneration restores some of the altered electrical properties of axotomized bullfrog B-cells

In bullfrog B-type sympathetic neurones axon injury produces substantial changes in somal membrane properties. These include a shortening of action potential afterhyperpolarization (AHP) and an increase in action potential (AP) duration. In the present experiments we compared two injury situations: nerve crush, which was followed by regeneration, and nerve cut, after which regeneration to the original target was prevented, to investigate whether these electrophysiological changes were related to axon regeneration. Both crush and cut injuries produced a similar maximum decrease in AHP duration (to 33 and 30%) by 14 days after axotomy. After nerve crush, AHP duration recovered to within control values by 42 days, while after cut it remained depressed. AHP amplitude decreased to the same extent after nerve crush or cut (to 62 and 58%), but the rate of decrease was slower following crush when compared with cut, and following both types of injury it still remained depressed at 42 and 49 days. Changes in AP duration also took longer to occur following nerve crush, reaching maximal values at 35-42 days, at which time AHP duration had returned to within the normal range. The early reduction in AHP duration and its rapid recovery in regenerating neurones suggests that the current underlying this membrane property is regulated by events associated with axon outgrowth and peripheral reconnection. In contrast, changes in AHP amplitude and AP repolarization appeared to be independent of the occurrence of axon regeneration and remained abnormal at 49 days despite the recovery of AHP duration. These results imply that the electrophysiological changes seen in B-cells following injury are differentially regulated during subsequent regeneration.     

AXOPLASMIC TRANSPORT OF CHOLINE ACETYLTRANSFERASE ACTIVITY IN MICE: EFFECT OF AGE AND NEUROTOMY

—We studied the axoplasmic transport of choline acetyltransferase (CAT) activity in sciatic nerves of normal mice of various ages. For at least 3 days after unilateral ligation of sciatic nerves of 6 and 30-week-old mice, the CAT activity in the ligated nerve increased as a linear function of time and the increase was confined to the 3 mm length of nerve immediately proximal to the ligature. The rate of increase of CAT activity in the ligated nerves of the 30-week-old mice was only 45 ± 6% that of the 6-week-old mice, whereas the CAT activity of non-ligated sciatic nerves of the older mice was 87 ± 6% more than that of the younger mice (n = 18, P < 0·001). The average velocity of axoplasmic transport of CAT activity was five times greater in the younger mice (1·5 ± 0·2 mm/day vs 0·3 ± 0·1 mm/day, n = 6, P < 0·01). Even greater differences were observed between still younger and older animals: the av velocity of axoplasmic transport of 2-week-old mice (3·5 ± 0·2 mm/day) was 17·5 times greater than that of 36-week-old mice (0·2 ± 0·1 mm/day). We also studied the axoplasmic transport of CAT activity in 6-week-old mice after unilateral section of the sciatic nerve. For at least 3 months after the operation, there were no differences between the sectioned nerves and the intact contralateral nerves with respect to the increase in CAT activity immediately proximal to a ligature placed at various times after neurotomy and one day before sacrifice. On the other hand, there was a reduction in the CAT activity of more proximal segments of the sectioned nerves. The reduction of CAT activity was maximal (52 ± 3%) 3 weeks after the operation when the maximum increase (2·5-fold) in the av velocity of axoplasmic transport of CAT activity was recorded (n = 6, P < 0·001). The inclusion of purified (100-fold) mouse brain CAT activity in the assays for the CAT activity of nerve segments demonstrated that the differences in content and rate of transport were not due to the presence of activators or inhibitors of CAT activity. These differences probably reflect physiologic changes in the axoplasmic transport of cholinergic neurons during development and regeneration.     

Reversal of axonal transport in regenerating nerves.

Abstract— Orthograde and retrograde axonal transport were studied in rat sciatic nerves which had been crushed and either allowed to regenerate, or prevented from doing so by tightly ligaturing the nerve. At various intervals after crushing the nerve. L-[³H]leucine was injected into the lumbosacral spinal cord. and the subsequent transport of labeled protein in motoneuron axons was quantitated by measuring the accumulation of labeled protein at collection crushes made proximal to the original nerve crush. Accumulations proximal to the collection crushes (orthograde transport) 9-11 h after injection (p.i.). decreased within I day of nerve injury, but returned to normal values as regeneration proceeded. In non-regenerating nerves accumulations remained depressed for at least 30 days. Accumulations distal to the collection crushes (retrograde transport) 9-11 h pi. increased over the first 5 days following injury but returned to normal values as regeneration proceeded. In non-regenerating nerves accumulations remained elevated. The time-course of retrograde transport of newly-synthesized protein also returned to normal during nerve regeneration. It is suggested that changes in retrograde transport during regeneration may inform the neuron cell body of the progress of regeneration and elicit appropriate metabolic responses. among which may be the changes in orthograde transport that follow axotomy.     

Increased regeneration rate in peripheral nerve axons following double lesions: Enhancement of the conditioning lesion phenomenon

The rate of regeneration of rat sciatic nerve sensory axons was measured using the pinch-reflex test method, and confirmed by studying the transport of labelled protein into the regenerating axons. For nerves receiving a single test crush lesion the rate was 4.02 ± 0.03 (SE) mm/day. For nerves with a conditioning lesion made at the knee seven days prior to the test lesion at the hip the rate was 5.73 ± 0.06 mm/day, and for nerves where both conditioning and test lesions were made at the same site (hip or knee) but separated by seven days, the rate was 6.76 ± 0.04 mm/day, a 68% increase over the normal rate, showing that pre-degeneration of the nerve distal to the site of the test lesion increases the rate of regeneration. It is concluded that the rate of axon regeneration can be influenced by the environment through which the regenerating axons grow.     

神经生长因子对兔坐骨神经损伤后脊髓前角运动神经元乙酰胆碱酯酶的影响

钳夹损伤兔右坐骨神经,于损伤处注射蛇毒ＮＧＦ４００Ｂｕ／ｋｇ／日,损伤术后１,３,７天和２,３,４,６,８周动态观察脊髓腰段伤侧第Ⅸ板层外侧群的大型运动神经元的ＡＣｈＥ活性改变。结果表明术后１,３天实验组（指损伤给药组）和对照组（指损伤对照组）ＡＣｈＥ活性均下降（Ｐ＞００５）;术后１,２,３周对照组ＡＣｈＥ活性明显下降,而实验组ＡＣｈＥ活性逐渐趋于恢复（Ｐ＜００１）;术后６周实验组ＡＣｈＥ活性恢复至正常水平（Ｐ＜００１）。本研究显示蛇毒ＮＧＦ对坐骨神经损伤后脊髓前角运动神经元ＡＣｈＥ活性恢复有促进作用,从而对运动神经元可起一定的保护作用和促进恢复的作用     

Impaired axonal regeneration in acrylamide intoxication

Acrylamide is a neurotoxin known to impair regeneration of axons following nerve crush and to produce structurally abnormal regenerating sprouts. To investigate the mechanism of these abnormalities, protein synthesis and fast axonal transport were studied in acrylamide-intoxicated and control rats 2 weeks after sciatic nerve crush. Using an in vitro preparation of sciatic nerve-dorsal root ganglion, there was no difference in ganglion ³H-leucine incorporation between the two groups. In these preparations of sensory axons, as well as in motor axons studied in vivo, a smaller proportion of rapidly transported radioactivity was carried beyond the crush in the acrylamide-regenerating nerves compared to the control-regenerating nerves. Correlative ultrastructural studies demonstrated that this difference reflected the impaired outgrowth of the acrylamide-regenerating nerves, rather than an abnormality in fast transport. The acrylamide-treated sprouts often developed swellings filled with whorls of neurofilaments; in addition, many sprouts ended in massively enlarged growth cones containing membranous organelles. EM autoradiography showed labeled, rapidly transported organelles accumulated in the neurofilamentous whorls, and therefore suggested that these organelles might be “trapped” or impeded in passage through these regions. However, there was no evidence that the growth cones received insufficient amounts of transported protein; in fact, the distended endings were densely labeled and apparently “ballooned” by transported organelles. These results suggest that acrylamide intoxication does not impair regeneration by diminishing the delivery of rapidly transported materials to the growing tip. Rather, the marked distention of the growth cones is interpreted as the morphological consequence of continued delivery of rapidly transported organelles into sprouts unable to utilize them in outgrowth.     

Transport of Muscarinic Cholinergic Marker Protein Activities in Regenerating Sciatic Nerve of Rat

The transport characteristics of choline acetyltransferase (ChAT; EC 2.3.1.6), acetylcholinesterase (AChE; EC 3.1.1.7), and the muscarinic acetylcholine receptors (mAChR) were studied in perineurally sutured, regenerating rat sciatic nerve. At different times after repair, the sciatic nerve was ligated for 24 h, and the activities of the cholinergic marker proteins, as well as the binding capacity, were measured proximally and distally from the ligature. The number of bidirectionally transported receptors increased linearly up to 5 months postoperatively (6.1-33.6% and 5.6-25.6% of the control level proximal and distal to the ligature, respectively). The quantity of anterogradely transported ChAT reached a plateau 3 months postoperatively (74.9% of the control level), whereas the retrogradely transported enzyme was then only 34.7% of the control value. The activity of AChE increased linearly during nerve regeneration, and exceeded the control level after 4 months (121.0% and 63.7% proximally and distally, respectively). The data indicate that the altered bidirectional transport of cholinergic marker proteins may be monitored quantitatively during nerve regeneration. This method might be suitable for studies of the nerve regeneration process.     

大白鼠交感节前神经再生的研究Ⅰ.生化、组化与功能观察

用液氮骤冻造成大白鼠交感节前神经变性后,通过神经末梢乙酰胆碱含量、胆碱酯酶活性测定以及电刺激交感干时外周反应等研究其再生规律。结果表明冻伤后3周内再生过程进展迅速,神经结构与功能均有相当程度的恢复;3周后再生过程转慢,直至一年时各指标仍远未达到正常。这证明交感节前神经的再生过程不同于中枢及其它外周神经而独具特征。     

Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor

When motoneuron axons in peripheral nerves are injured, the expression of the p75 low-affinity neurotrophin receptor (p75) increases in their cell bodies and axons, as well as in the Schwann cells undergoing Wallerian degeneration in the distal excised nerve segment. To understand the role of p75 in the events following nerve injury, we have examined the survival and regeneration of motoneurons in mice lacking the p75 receptor. In adult p75 (−/−) mice, functional recovery of whiskers movement following a facial nerve crush occurred slightly earlier than in p75 (+/+) mice, and some recovery of function over a 25-day interval following a nerve cut occurred more frequently in p75 (−/−) mice. Motoneuron profile numbers were slightly reduced in p75 (−/−) mice, and there were correspondingly fewer axons in the facial nerve. At 25 days following axotomy, profile survival in the adult p75 (−/−) mice was significantly improved compared to p75 (+/+) mice (mean 85% ± standard error of the mean 3%, n = 11 vs. 67 ± 5%, n = 11 in CD-1 mice and 68.0 ± 4%, n = 6 in balb/c mice), and significantly more regenerating axons were present in the distal facial nerve. After axotomy on postnatal day 1, there was almost total loss of motoneuron profiles in the lateral facial nucleus in p75 (+/+) mice (1.7 ± 0.3% remained, n = 5), while significantly more survived in p75 (−/−) mice (17 ± 2.5%, n = 6) . We conclude that expression of p75 in motoneurons or Schwann cells following facial nerve injury is not necessary for motoneuron survival or prompt regeneration of their axons; rather, p75 may increase their risk of dying. © 1998 John Wiley & Sons, Inc. J Neurobiol 34: 1–9, 1998     

神经生长因子促进坐骨神经再生修复的酶组织化学研究

目的研究对兔右坐骨神经损伤后局部给予蛇毒神经生长因子(NGF),观察坐骨神经酶活性变化和超微结构的恢复情况,探讨NGF对神经再生的影响.方法乙酰胆碱酯酶(AChE)、酸性磷酸酶(ACPase)的酶组织化学技术和电镜技术.结果神经损伤后:AChE活性明显下降,NGF组的AChE活性恢复快于盐水对照组;ACPase活性逐渐增高,NGF组的ACPase活性恢复时间短于盐水对照组.坐骨神经的超微结构在神经损伤后也发生变化,NGF组的变化程度小于盐水对照组,恢复时间短于对照组.结论NGF可通过影响酶物质的代谢而起到加快受损神经恢复的作用.为临床上应用蛇毒NGF治疗周围神经损伤提供形态学依据.     

Transport of proteins, glycoproteins and cholinergic enzymes in regenerating hypoglossal neurons

The accumulation of [³H]leucine- and [³H]fucose-labelled axonal proteins, acetyl-CoA : choline O-acetyltransferase (ChAc, EC 2.3.1.6) and acetylcholinesterase (AChE, EC 3.1.1.7) was studied proximal to a ligature applied to the hypoglossal nerve of the rabbit at different phases of nerve regeneration. After 1 week of regeneration, the accumulation of rapidly migrating [³H]leucine-labelled proteins, ChAc and AChE was reduced as compared to that of the contralateral nerve. In contrast, the accumulation of [³H]fucose-labelled glycoproteins was markedly increased. After a regeneration period of 4-6 weeks, the accumulation of proteins and glycoproteins in the regenerating nerve was increased whereas the accumulation of ChAc and AChE was almost normal. The results indicate an initial depression of the synthesis and axonal transport of the bulk of rapidly migrating proteins, ChAc and AChE in the chromatolytic hypoglossal neurons whereas the synthesis and transport of rapidly migrating glycoproteins is increased. These initial changes are less pronounced during the subsequent regeneration period.     

FAST AXOPLASMIC TRANSPORT OF ACETYLCHOLINESTERASE IN MAMMALIAN NERVE FIBRES

Abstract— Acetylcholinesterase (acetylcholine acetyl-hydrolase, EC 3.1.1.7) is carried down mammalian nerve fibres by the fast axoplasmic transport system. This conclusion was derived from experiments involving the ligation of cat sciatic nerves at two sites placed 83.5 mm apart. The enzyme accumulated in segments of nerve proximal to the upper ligation in a linear fashion over a period of at least 20 h. At approximately 5 h the accumulation of enzyme ceased in the nerve segment proximal to the distal ligation within the isolated length of nerve, an observation indicating that the portion of AChE free to move within the isolated nerve had been depleted during this period of time. The freely moving fraction of AChE was estimated to be 15% of the total enzyme activity present in the nerve (10% in the proximo-distal direction and 5% in the retrograde direction). The rate of AChE downflow (as estimated from the intercept of the curve plotting accumulation with the line denoting when depletion started) was 431 mm/day within a 95% confidence interval of 357–543 mm/day. In view of the variability, our results demonstrated that AChE was being carried by the fast axoplasmic transport system, which in earlier studies was estimated to have a characteristic rate close to 410 mm/day.
An accumulation of AChE was also found on the distal side of the ligations that represented a movement of AChE in the distal-proximal direction in the fibres. This retrograde transport was smaller in amount (about one-half) than the proximo-distal rate of transport, or close to 220 mm/day. The rate of AChE transport was discussed in relation to the 'transport filament' hypothesis of fast axoplasmic transport.     

Bidirectional axonal transport of 16S acetylcholinesterase in rat sciatic nerve

Axonal transport of the 16S Molecular form of acetylcholinesterase (16S-AChE) in doubly ligated rat sciatic nerves was studied by means of velocity sedimentation analysis on sucrose gradients. This form of AChE was selectively confined to motor, and not to sensory, fibers in the sciatic nerve, where it represented 3--4% of total AChE. Its activity increased linearly with time (4--20 hr) in nerve segments (7 mm) proximal to the central ligature (4.5 mU/24hr) and distal to the peripheral ligature (2.0 mU/24 hr). From the linear rates of accumulation of 16S-AChE, we conclude that the enzyme is conveyed by anterograde and retrograde axonal transport at velocities close to those previously defined for the movement of total AChE (410 mm/day, anterograde; 220 mm/day, retrograde). The transport of AChE molecular forms, other than the 16S form, could not be resolved presumably due to their presence in blood as well as at extraaxonal sites. The present findings are consistent with the view that in rat sciatic nerve most, if not all, of the small portion of total AChE (approximately 3%) which is transported may be accounted for by 16S-AChE.     

Incorporation of axonally transported glycoproteins into axolemma during nerve regeneration

The insertion of axonally transported fucosyl glycoproteins into the axolemma of regenerating nerve sprouts was examined in rat sciatic motor axons at intervals after nerve crush. [(3)H]Fucose was injected into the lumbar ventral horns and the nerves were removed at intervals between 1 and 14 d after labeling. To follow the fate of the “pulse- labeled” glycoproteins, we examined the nerves by correlative radiometric and EM radioautographic approaches. The results showed, first, that rapidly transported [(3)H]fucosyl glycoproteins were inserted into the axolemma of regenerating sprouts as well as parent axons. At 1 d after delivery, in addition to the substantial mobile fraction of radioactivity still undergoing bidirectional transport within the axon, a fraction of label was already associated with the axolemma. Insertion of labeled glycoproteins into the sprout axolemma appeared to occur all along the length of the regenerating sprouts, not just in sprout terminals. Once inserted, labeled glycoproteins did not undergo extensive redistribution, nor did they appear in sprout regions that formed (as a result of continued outgrowth) after their insertion. The amount of radioactivity in the regenerating nerves decreased with time, in part as a result of removal of transported label by retrograde transport. By 7-14 d after labeling, radioautography showed that almost all the remaining radioactivity was associated with axolemma. The regenerating sprouts retained increased amounts of labeled glycoproteins; 7 or 14 d after labeling, the regenerating sprouts had over twice as much of radioactivity as comparable lengths of control nerves or parent axons. One role of fast axonal transport in nerve regeneration is the contribution to the regenerating sprout of glycoproteins inserted into the axolemma; these membrane elements are added both during longitudinal outgrowth and during lateral growth and maturation of the sprout.     

Polysialyltransferase overexpression in Schwann cells mediates different effects during peripheral nerve regeneration

The polysialic acid (PSA) moiety of the neural cell adhesion molecule (NCAM) has been shown to support dynamic changes underlying peripheral nerve regeneration. Using transgenic mice expressing polysialyltransferase ST8SiaIV under control of a glial-specific (proteolipid protein, PLP) promoter (PLP-ST8SiaIV-transgenic mice), we tested the hypothesis that permanent synthesis of PSA in Schwann cells impairs functional recovery of lesioned peripheral nerves. After sciatic nerve crush, histomorphometric analyses demonstrated impaired remyelination of regenerated axons at the lesion site and in target tissue of PLP-ST8SiaIV-transgenic mice, though the number and size of regenerating unmyelinated axons were not changed. This was accompanied by slower mechanosensory recovery in PLP-ST8SiaIV-transgenic mice. However, the proportion of successfully mono-(re)innervated motor endplates in the foot pad muscle was significantly increased in PLP-ST8SiaIV-transgenic mice when compared with wild-type littermates, suggesting that long-term increase in PSA levels in regenerating nerves may favor selective motor target reinnervation. The combined negative and positive effects of a continuous polysialyltransferase overexpression observed during peripheral nerve regeneration suggest that an optimized time- and differentiation-dependent control of polysialyltransferase expression in Schwann cells may further improve recovery after peripheral nerves injury.