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PubMed1989

Mechanism of T cell proliferation in vivo: analysis of IL-2 receptor expression and activation of c-myc and c-myb oncogenes during lymphatic regeneration.

The mechanism of T cell proliferation was studied using in vivo lymphatic regeneration as the model. Lymphatic regeneration was induced by injecting a sublethal dose (300 mg/kg) of cyclophosphamide (Cy) into mice. Majority of the regenerating splenic T cells were found to be in the cell cycle, nearly 30% being found in S/G2+M phases resembling the ratio obtained for mitogen activated T cells in vitro. Expression of interleukin-2 receptor (IL-2R) was defined by the monoclonal anti-IL-2R antibody, AMT-13. Only 1-3% of regenerating T cells were IL-2R positive (while about 30% of the in vitro activated T cells were IL-2R positive). Accordingly, these cells did not respond to IL-2 in vitro. However, when the freshly isolated regenerating T cells were cultured in the presence of Con A or PMA + ionophore A 23187, IL-2R was readily induced. The regenerating T cells were further analyzed for the expression of the cellular oncogenes c-myc and c-myb. These cells expressed about three times more c-myb mRNA than Con A-stimulated T cells and the levels were comparable to those seen in thymocytes. By contrast, the amount of c-myc mRNA was similar in the regenerating T cells and in Con A-activated T cells, but weak or barely detectable in splenocytes and thymocytes. Taken together, our results imply that the vigorous T cell proliferation during cyclophosphamide-induced lymphatic regeneration is independent of the IL-2/IL-2R hormone system, like T-cell precursor proliferation in the thymus, and is characterized by both high c-myb expression typical for thymocytes and high c-myc expression typical for in vitro proliferation-activated T cells.

Animals↗
PubMed1977

Axonal transport of putrescine, spermidine and spermine in normal and regenerating goldfish optic nerves.

Radopactove putrescine, spermidine or spermine was injected into the right eye of normal goldfish and fish in which both optic nerves had been crushed 18 days earlier. Fish were sacrificed 0.25-21 days after injection. Trichloroacetic acid-soluble and -insoluble material was extracted from the right retina and both tecta and assayed for radioactivity (significant differences between left and right tecta suggesting axonal transport). The nature of the radioactivity in the TCA-soluble fraction was determined on an amino acid analyzer. Results indicate that putrescine is not axonally transported in intact goldfish optic nerves, but that during regeneration of the optic nerve large amounts of putrescine are axonally transported at rates similar to the fast component of protein transport. Spermidine appears to be axonally transported both in intact optic nerves and in regenerating optic nerves, and at an intermediate rate of transport; the amount of spermidine transported is significantly increased during regeneration. Spermine is also axonally transported in intact and regenerating nerves, at a rate similar to the rapid rate of protein transport. The amount of spermine transported appears to be slightly less in regenerating than in intact nerves during early stages of regeneration, but increases during later stages of nerve regeneration. The results suggest that putrescine and spermidine may be preferentially transported during nerve regeneration, while spermine and spermidine are transported extensively in intact nerves.

Animals↗
PubMed1984

Competence of nerve tissue as distal insert promoting nerve regeneration in a silicone chamber.

A new peripheral nerve forms across a 10 mm gap within a silicone chamber regeneration model when the distal segment of a transected sciatic nerve, connected to its end organs, is sutured into the distal end of the chamber. We have tested the ability of other tissue inserts to support axonal regeneration in the chamber. When an isolated 2 mm piece of sciatic nerve was sutured into the distal end, fibrin matrix formation, cell immigration and axonal regeneration were identical to those occurring in the control. When the distal nerve insert was replaced with a 2 mm piece of skin or a ligation, a matrix did not form and subsequent cell immigration and axonal regeneration did not occur. When a 2 mm piece of tendon was inserted, a matrix did form at 1 week, but a structure across the gap was observed at later time periods in only 2 out of 7 chambers. The matrix either dissolved before cells could enter the chamber or did not promote cellular immigration and subsequent axonal regeneration. When the distal end was left open, a matrix formed and cells from the reactive tissue outside the chamber entered the matrix and formed a granulation tissue bridge across the gap. This tissue failed to support axonal regeneration; at 3 weeks, axons stopped 1 mm beyond the proximal stump at the interface with the granulation tissue. Thus, matrix formation and a cellular bridge are necessary but not sufficient to ensure regeneration. Successful regeneration across the silicone chamber gap requires humoral and/or cellular contributions available from peripheral nervous tissue and not from the other tested tissues.

Animals↗
PubMed1985

The effect of a conditioning lesion on the regeneration rate of peripheral nerve axons containing substance P.

The regeneration rate of peripheral nerve axons containing substance P-like immunoreactivity (SPLI) was measured in rat sciatic nerve by radioimmunoassay of SPLI in nerve segments 2, 4 and 6 days after a test lesion made by briefly crushing the nerve at the hip. The regeneration rate of the fastest growing sensory axons was also measured in the same nerves using the pinch-reflex procedure. Three groups of animals were compared: group S, which received only the single test lesion, had regeneration rates of 3.57 +/- 0.26 (S.E.) mm/day for SPLI-containing axons and 3.53 +/- 0.14 mm/day for the fastest growing sensory axons. Group A/H, which received a conditioning lesion on the tibial nerve at the ankle 7 days prior to the test lesion at the hip, had a regeneration rate for SPLI-containing axons which was not significantly different from group S, of 3.35 +/- 0.17 mm/day. However, the regeneration rate for the sensory axons was significantly increased to 4.60 +/- 0.23 mm/day. Group H/H, which received both conditioning and test lesions at the hip, once again separated by 7 days, showed a significant increase in regeneration rate of SPLI-containing axons to 5.50 +/- 0.33 mm/day and a further increase over group A/H in the regeneration rate of sensory axons to 6.70 +/- 0.25 mm/day. We conclude that the small-diameter, unmyelinated axons containing SPLI in peripheral nerve normally regenerate at the same rate as the fastest growing sensory axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Electrophysiological study of conditioning lesion effect on rat sciatic nerve regeneration following either prior section or freeze. I. Intensity and time course.

A peripheral nerve lesion performed distally prior to a proximal axotomy is known to result in an increase in the rate of regeneration of both sensory and motor fibres. This phenomenon is called the 'conditioning lesion effect'. The aim of this study was to determine whether or not the kind of the conditioning lesion influences the intensity and the time course of the conditioning lesion effect. The prior lesion was performed on the tibial nerve of rats at the ankle either by cutting the nerve or freezing it by means of a 1 mm diameter liquid nitrogen cryod. At several points in time up to 28 days a second (or test) lesion consisting of a freeze was performed on the sciatic nerve at the middle part of the thigh. The regeneration of the fastest growing fibres of the sciatic nerve was measured electrophysiologically 5, 7 and 9 days after the test lesion. The nerve was surgically removed, immediately mounted in a recording nerve chamber and stimulated proximally to the test lesion. The distance between the test lesion and the most distal point where an evoked nerve potential was detectable was taken as the regenerated nerve length. Then the rate of regeneration was calculated and the initial delay was estimated by means of a linear regression plotting the regenerated nerve lengths against the days of recording. All the results were compared to those of a control group where the test lesion alone was performed. The increase in the maximal rate of regeneration was greater following a prior section (+25%) than following a prior freeze (+12%). Following a prior section, the rate of regeneration began to be significantly increased for a conditioning interval of 4 days, and went on until a conditioning interval of 28 days. By contrast, after a prior freeze the rate of regeneration was significantly increased solely for an interval of 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Embryonic and regenerating Xenopus retinal fibers are intrinsically different.

Growth and guidance behavior of Xenopus embryonic (ER) (optic vesicle stage 25/26) and regenerating retinal fibers (stage 47/50 newly regenerating NR, and actively regenerating RR, respectively) have been studied in vitro on a variety of substrates in serum-free media. RR retinas receive a prior conditioning lesion 12-14 days before explantation while NR retinas are explanted immediately after axotomy. The substrates include plastic (UN), polylysine (PL), polyornithine (PO), laminin (LM), fibronectin (FN), and collagen type I (CO). Two kinds of experimental situations were tested, one in which substrates were derivatized to plastic as a planar surface, while the second involved the addition of a substrate as a soluble supplement to dishes derivatized with PL. A neurite growth index (NGI), based on density of neurite outgrowth and axon lengths, is determined for each fiber type on all substrates. Embryonic and regenerating fibers are phenotypically different fiber types; each displays a specific "substrate preference profile" (SPP), reflecting differential growth on each substrate. ER neurites grow equally well on all planar substrates, including plastic, but do not grow on CO (SPP, LM = FN = PL = PO = UN greater than CO). Both NR and RR neurites show distinct substrate preferences, but RR neurites grow more vigorously (SPP, LM greater than CO greater than PL = PO greater than FN). In media supplemented with LM, FN or CO, the SPPs showed little change but the neurite bundle patterns were qualitatively different. Only regenerating neurites display clockwise growth in laminin (LM) and fibronectin (FN)-supplemented media. Under no conditions do embryonic fibers exhibit this pattern which suggests that embryonic and regenerating retinal fibers also differ in cytoskeletal organization. Evidence of intrinsic growth differences in vitro suggest that embryonic and regenerating retinal fibers may not respond to identical guidance cues during in vivo development and regeneration of retinotectal connections.

Animals↗
PubMed1987

Immunochemical analysis of protein isoforms in thick myofilaments of regenerating skeletal muscle.

The expression of myosin heavy chain (MHC) and C-protein isoforms has been examined immunocytochemically in regenerating skeletal muscles of adult chickens. Two, five, and eight days after focal freeze injury to the anterior latissimus dorsi (ALD) and posterior latissimus dorsi (PLD) muscles, cryostat sections of injured and control tissues were reacted with a series of monoclonal antibodies previously shown to specifically bind MHC or C-protein isoforms in adult or embryonic muscles. We observed that during the course of regeneration in each of these muscles there was a reproducible sequence of antigenic changes consistent with differential isoform expression for these two proteins. These isoform switches appear to be tissue specific; i.e., the isoforms of MHC and C-protein which are expressed during the regeneration of a "slow" muscle (ALD) differ from those which are synthesized in a regenerating "fast" muscle (PLD). Evidence has been obtained for the transient expression of a "fast-type" MHC and C-protein during ALD regeneration. Furthermore, during early stages of PLD regeneration this muscle contains MHCs which antigenically resemble those found in the pectoralis muscle at embryonic and early posthatch stages of development. Both regenerating muscles express an isoform of C-protein which appears immunochemically identical to that normally expressed in embryonic and adult cardiac muscle. These results support the concept that isoform transitions in regenerating skeletal muscles qualitatively resemble those found in developing muscles but differences may exist in temporal and tissue-specific patterns of gene expression.

Actin Cytoskeleton↗
PubMed1992

Differential proliferative response of cultured fetal and regenerating hepatocytes to growth factors and hormones.

Upon epidermal growth factor (EGF) stimulation, fetal (20 days of gestation) and regenerating (44-48 h after partial hepatectomy) rat hepatocytes, isolated and cultured under identical conditions, increased DNA synthesis and entered into S-phase and mitosis, measured as [3H]thymidine incorporation and DNA content per nucleus in a flow cytometer, respectively. Fetal hepatocytes consisted of a homogeneous population of diploid (2C) cells. Two different populations of cells were present in regenerating liver, diploid (2C) and tetraploid (4C) cells, that responded to EGF. Glucagon or norepinephrine did not affect EGF stimulation of DNA synthesis in fetal liver cells, but they potentiated EGF response in regenerating hepatocyte cultures. Glucocorticoid hormones (dexamethasone) inhibited DNA synthesis in fetal hepatocyte cultures, an effect potentiated by the presence of glucagon or norepinephrine. In contrast, in regenerating hepatocytes, dexamethasone increased EGF-induced proliferation. EGF-dependent DNA synthesis was inhibited by TGF-beta in both fetal and regenerating cultured hepatocytes. TGF-beta action was partially suppressed by norepinephrine in regenerating hepatocytes, but was without effect in fetal hepatocyte cultures, whereas a synergistic action between TGF-beta and dexamethasone inhibiting growth in fetal but not in regenerating hepatocytes was found. Taken together, these results may suggest that there are significant differences between fetal and regenerating hepatocyte growth in their response to various hormones.

Animals↗
PubMed1992

Oligodendrocyte- and myelin-associated inhibitors of neurite outgrowth: their involvement in the lack of CNS regeneration.

Until now central nervous system (CNS) neurites have been thought to have little capacity for regeneration following a lesion. When allowed to grow into peripheral nervous system (PNS) grafts, however, lesioned CNS axons are known to regenerate. Recently, an inhibitory substrate effect of CNS myelin and oligodendrocytes has been discovered which could be directly involved in the lack of regeneration. In culture, neurite growth cones were shown to specifically arrest their movement when contacting oligodendrocyte processes. The inhibitory components were characterized as two proteins of 35 and 250 kDa. A specific monoclonal antibody was generated (IN-1) that could neutralize these inhibitory effects. The role of the inhibitors in CNS regeneration was investigated in young rats receiving lesions of the corticospinal tract and implanted with a source of IN-1 mAB or control mAB. Results showed clear regeneration to over 10 mm in 2-5 weeks in IN-1 mAB-treated animals, while no fibers were detected further than 1 mm caudal to the lesion in controls. A similar, highly significant enhancement of regeneration was also found for the cholinergic septohippocampal pathway and for the optic nerve. These results show that lesioned CNS neurons can regenerate in CNS tissue when specific myelin components are neutralized, thus demonstrating that these inhibitory components play a crucial role in the lack of CNS regeneration.

Acetylcholinesterase↗
PubMed1995

Neural regeneration and neuronal migration following injury. I. The endocrine hypothalamus and neurohypophyseal system.

Central to this investigation are several basic hypotheses that are designed to test the role of nitric oxide (NO) in the complex process of central regeneration and plasticity in a well established model system of the mammalian brain. We have employed histochemical techniques at the light and ultrastructural level coupled with correlative scanning electron microscopy, immunoelectron microscopy, and in situ hybridization in order to determine the functional significance of the increased expression of nitric oxide synthase (NOS) in neurons of the supraoptic (SON) and paraventricular (PVN) nuclei which accompanies regeneration of their axotomized neurites following hypophysectomy. The aim of this investigation was to determine the potential role and temporal up-regulation of NOS in this basic regenerative process and to establish the ultrastructural and neuroanatomical correlates during critical periods of regeneration and regrowth of SON and PVN axons following hypophysectomy in the endocrine hypothalamus of the rat. Our data support the hypothesis that NO may serve as a second messenger molecule that may act in some fashion to govern not only the process of central regeneration and regrowth of magnocellular (SON/PVN) axons into the median eminence, neural stem, and neural lobe (the neurohypophyseal system) but may also influence the regeneration of neurites into new neuroanatomical domains such as the adjacent lumen of the third cerebral ventricle. We have demonstrated a distinct temporal relationship between injury (axotomy) of SON/PVN axons and the establishment of new neurovascular zones following hypophysectomy with the up-regulation of NOS. This up-regulation appears to correlate well with successful regeneration in the mammalian neurohypophyseal system. We have also successfully inhibited axonal regeneration with the use of nitroarginine, a competitive antagonist of NO. NOS up-regulation attendant to regeneration of SON and PVN axons may have inestimable clinical implications, particularly with respect to closed head injury and cerebral contusion that involves the mechanical shearing of the infundibular stalk. In addition, this investigation has reaffirmed that large numbers of bona fide neurons migrate and emerge upon the floor of the adjacent third cerebral ventricle shortly following hypophysectomy (within 2 weeks). The origin and mechanisms of neuronal migration and plasticity following hypophysectomy are the subject of interpretation and discussion in this investigation.

Amino Acid Oxidoreductases↗
PubMed1987

Role of ecdysone and eyestalk factors in regulating regeneration in larval crustaceans.

Megalopae of the mud crab Rhithropanopeus harrisii can regenerate autotomized limbs. Regeneration during the megalopal stage required a significant delay in ecdysis to the first crab. Megalopae that failed to initiate regeneration complete ecdysis significantly faster than do controls. Exposure of intermolt- and premolt-stage megalopae to exogenous ecdysone significantly reduced (greater than or equal to 30%) the number of animals completing regeneration. The regeneration-induced delay in ecdysis was not significantly different in animals exposed to ecdysone. The molt cycle of nonregenerating megalopae exposed to ecdysone was further accelerated. Eyestalk ablation did not significantly reduce the molt cycle duration of regenerating animals. Eyestalkless nonregenerating animals did not display accelerated ecdysis. It is hypothesized that two additional hormonal factors are involved in "fine tuning" the molt cycle of regenerating animals. One located outside the eyestalks extends the molt cycle to accommodate regeneration. The second factor accelerates ecdysis in nonregenerating animals and appears to be produced in the eyestalks.

Animals↗
PubMed1989

Is the pineal involved in the stimulatory influence of prolactin on tail regeneration in lizards? Studies with exogenous prolactin in lizards exposed to continuous darkness.

We have recently demonstrated that continuous light stimulates tail regeneration in the gekkonid lizard, Hemidactylus flaviviridis, whereas continuous darkness and pinealectomy depress regeneration. As a sequel to this observation, the effect of exogenous ovine prolactin (oPRL) on tail regeneration in normal (NL) and pinealectomized (PX) Hemidactylus exposed to continuous darkness (L:D 0:24) during the monsoon season was investigated. Once-daily intraperitoneal (ip) injections of 500 micrograms/kg oPRL were administered to a group of NL lizards, a group of PX lizards, and a group of sham-PX (sPX) lizards, 5 days prior to tail autotomy and 50 days afterward. Three groups--PX, sPX, and NL animals--served as the controls and received once-daily ip injections of 0.6% saline. Our observations show that initiation of regeneration, daily growth rate, total length of new growth (regenerate) at the end of regeneration, and total percentage replacement of lost (autotomized) tail were all significantly enhanced in oPRL-treated NL lizards as compared with their saline-treated (NL, PX, and sPX) and oPRL-treated (PX and sPX) counterparts. It is suggested that PRL may be the active factor that speeds up the rate of tail regeneration in lacertilians. The role of the pineal organ in vertebrate photoreception and the possibility that in Hemidactylus the presence of an intact pineal is somehow linked with the favorable influence of PRL on tail regeneration are discussed.

Animals↗
PubMed1985

Comparative neurotoxicity of tubulin-binding drugs: inhibition of goldfish optic nerve regeneration.

Intraperitoneal or intraocular (io) injection of tubulin-binding drugs in goldfish, Carassius auratus L., inhibited axonal regeneration or restoration of functional synapses in optic axons following optic nerve crush. One eye was used to detect effects on regeneration and the other was kept intact to detect effects on maintenance of established optic circuits. Regeneration was assessed by measuring the time to reappearance of a visually evoked branchial suppression response. Three drugs, vincristine, vinblastine, and podophyllotoxin, administered semiweekly by ip injection, each inhibited regeneration at doses that did not impair maintenance of response. Similar results were previously reported for ip colchicine. Vincristine was several times more potent than podophyllotoxin or colchicine and 25 times more potent than vinblastine. Picropodophyllotoxin, an isomer of podophyllotoxin which has low affinity for tubulin, did not inhibit regeneration. The io experiments showed that maintenance of vision was reversibly inhibited by a single injection of 0.05 micrograms/g of colchicine but unaffected by 0.01 microgram/g, and that administration of the lower dose immediately following optic nerve crush inhibited regeneration. Intraocular lumicolchicine, a colchicine photoisomer which has low affinity for tubulin, did not inhibit maintenance or regeneration. In contrast, an io dose of vincristine sufficient to inhibit visual recovery also blocked maintenance of vision. Thus regeneration and maintenance effects could not be dissociated for io vincristine suggesting its mechanism of action on retinal cells is different. A conditioning lesion was shown to decrease the time to reappearance of the visually evoked branchial response following optic nerve crush, which indicates that it is a sensitive index of the rate of axonal outgrowth to the optic tectum.

Analysis of Variance↗
PubMed1993

Insulin-like growth factor II increases the rate of sciatic nerve regeneration in rats.

A slow rate of nerve regeneration conspires together with atrophy and degeneration of denervated organs to increase the risk of permanent disability following injury to the mammalian peripheral nervous system. Therefore, it is of both practical and theoretical interest to identify those endogenous factors that determine the spontaneous velocity of nerve regeneration, and to discover exogenous factors which hold promise for augmenting the rate. We report that locally infused insulin-like growth factor II significantly increases the speed of sensory axon regeneration in rat sciatic nerves. It appeared that 1 microgram/ml insulin-like growth factor II acted through insulin-like growth factor receptors, because a comparable concentration of insulin had little effect. Furthermore, there was a sustained reduction in regeneration rate when an anti-insulin-like growth factor II antiserum was continuously infused near a window in the epineurium located just below a site of nerve crush, indicating that the spontaneous regeneration rate was continuously dependent on endogenous insulin-like growth factor activity. These results show that exogenously administered insulin-like growth factor II can increase the rate of peripheral nerve regeneration, and that the endogenous insulin-like growth factors in nerves are required to maintain the normal rate of regeneration. These in vivo data complement previous observations showing that insulin-like growth factors can increase neurite outgrowth in cultured neurons, and that insulin-like growth factor II gene expression is correlated with synapse development. They further support the hypothesis that insulin-like growth factors play a role in nerve regeneration.

Animals↗
PubMedDate not supplied

Nerve fiber regeneration following axotomy in the diabetic biobreeding Worcester rat: the effect of ARI treatment.

Diabetic neuropathy is characterized by progressive nerve fiber degeneration resulting in nerve fiber loss. In order to examine what role impaired nerve fiber regeneration may play in the progressive net nerve fiber loss, spontaneously diabetic biobreeding Worcester (BB/W) rats were subjected to sciatic nerve axotomy at 6 weeks of diabetes. Myelinated nerve fiber regeneration was examined morphologically and morphometrically at various time points following axotomy. The data were compared with those of axotomized control rats and diabetic rats treated with an aldose reductase inhibitor (ARI) from 1 week after onset of diabetes. Diabetic rats showed a significant attenuation of nerve fiber regeneration during the first 6 weeks following axotomy, which was normalized at 4 months postaxotomy. ARI treatment resulted in an initial burst of supranormal regeneration, which was normalized at 4 months postaxotomy. Impaired nerve fiber regeneration in diabetic rats was associated with a marked delay in preceding Wallerian degeneration and decreased phagocytic activity by macrophages, changes not demonstrated in ARI-treated diabetic rats. We propose that the impaired nerve fiber regeneration in the diabetic BB/W rat may, in part, be the result of impaired recruitment and/or function of macrophages necessary for the initiation of normal nerve fiber regeneration. The corrective effects of ARI treatment on the regenerative ability of diabetic peripheral nerve suggest that an activated polyol pathway may impact on both intrinsic and extrinsic mechanisms governing nerve fiber regeneration.

Aldehyde Reductase↗
PubMed2006

Is there any effect of renal failure on the hepatic regeneration capacity following partial hepatectomy in rats?

The effects of renal dysfunction on liver regeneration capacity have not been fully elucidated before, although many patients with renal failure are subjected to hepatectomy due to hepatobiliary diseases. In this study, we sought to determine the effects of renal dysfunction on the hepatic regeneration capacity using rat chronic renal failure model. After establishing chronic renal failure (CRF group) by semi-total renal resection, the rats were subjected to 70% partial hepatectomy (PHx). Rats without renal failure were used as control (Sham group). The hepatic regeneration rate, histology of the liver, clearance of indocyanine green into the bile, and the expression of hepatic regeneration-associated genes in the liver were evaluated. The hepatic regeneration rate was lower in CRF group as compared to Sham group on day 1 after PHx. Mitotic index evaluated by histologic examination on day 1 after PHx was also significantly lower in CRF group. However, no difference in these indices was observed on day 2 and 7 between Sham and CRF. Indocyanine green clearance rate was almost identical between Sham and CRF on day 7 following PHx. The baseline expressions of the hepatic regeneration-associated genes, such as IL-6, TNF-alpha, HGF, c-fos, and c-jun, in the liver of CRF were significantly lower than those of Sham. However, the rate of upregulation of these genes was not significantly different between Sham and CRF. These results clearly demonstrate that the renal dysfunction, although initially delays the onset, does not suppress the total hepatic regeneration capacity following partial hepatectomy. The function of the regenerated liver on day 7 after PHx also was not different. Our results provide a possibility that the hepatectomy can be indicated even for the patient with a chronic renal failure.

Animals↗
PubMed2006

Evidence for Notch signaling involvement in retinal regeneration of adult newt.

Involvement of Notch signaling in retinal regeneration by transdifferentiation of pigment epithelium cells was investigated using the adult newt Cynops pyrrhogaster. During retinal regeneration, cells expressing Notch-1 first appeared in the regenerating retina one to two cells thick (stage E-3) originated from the retinal pigment epithelium (RPE) cells, and increased in number as the regenerating retina increased in thickness. Notch-1 expression was decreased in the central retina in association with cell differentiation and became restricted to the peripheral retina. Administration of a Notch signaling blocker DAPT resulted in the appearance of a cluster of neurons, earlier than in normal regeneration, along the regenerating retina 1-3 cells thick (stage E-3 to I-1). Immunoblot analysis suggested that DAPT could perturb the processing of Notch-1. Similar results were obtained in the newt embryonic retinal development. These results suggest that the Notch-1 signaling system may be reset to regulate neurogenesis during retinal regeneration. However, PCR analysis revealed that the adult newt RPE cells express Hes-1, neurogenin1 and sometimes Delta-1 Hes-1, neurogenin1 and sometimes Delta-1 all of which are differently regulated in association with retinal regeneration, implying that Notch signaling might also be involved early in the process of transdifferentiation.

Animals↗
PubMed2005

Changes in somatic sodium currents of ganglion cells during retinal regeneration in the adult newt.

Adult newts can regenerate their entire retinas following a complete removal of the original tissues. During retinal regeneration, ganglion cells differentiate first from the progenitor cells, and develop their capability of spike firing. In the present study, to understand the process of functional differentiation of ganglion cells, we investigated alterations of their voltage-gated sodium currents during retinal regeneration by a whole-cell patch-clamp technique. To minimize space clamp errors, sodium currents were recorded from neurite-free somata of presumptive ganglion cells that were mechanically isolated from living slices of regenerating retinas at different morphological stages. During retinal regeneration, the somatic sodium current density was increased 2.6-fold (48 to 123 pF/pA) and the half-activating voltage was shifted slightly to more hyperpolarizing membrane potentials (-10 to -13 mV), while steady-state inactivation was not changed obviously. Curve fitting analysis of currents revealed that the sodium current consists of two components with different inactivation time constants. During retinal regeneration, the ratio of slow to fast inactivating current component was increased 2.6-fold (0.11 to 0.29). These results suggest that the somatic sodium currents of ganglion cells may undergo modifications of their voltage dependence and kinetic properties during retinal regeneration. A small number of the presumptive ganglion cells in regenerating retinas with a segregating inner plexiform layer exhibited sodium currents comparable to those in the normal retina. This might suggest that maturational regulation of sodium channel function starts during a period of synaptic layer formation within the retina.

Action Potentials↗