Deafferentation-induced apoptosis of neurons in thalamic somatosensory nuclei of the newborn rat: critical period and rescue from cell death by peripherally applied neurotrophins (original) (raw)
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Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1993
We have studied the effect of human recombinant neurotrophin-4/5 (NT-4/5) on the survival of developing PNS neurons from embryonic mice and chickens. NT-4/5 transiently supported mouse NGF-dependent trigeminal and jugular neurons at early stages of target field innervation and mouse brain-derived neurotrophic factor (BDNF)-dependent no-dose neurons during the phase of naturally occurring cell death. NT-4/5 was as potent as BDNF in supporting the survival of these neuronal populations. Surprisingly, NT-4/5 was 3 orders of magnitude less potent than BDNF as a survival factor for early chick dorsomedial trigeminal sensory neurons and did not support the survival of chick BDNF-dependent trigeminal mesencephalic or ventrolateral trigeminal sensory neurons at any of the developmental stages tested. Thus, NT-4/5 is a survival factor for certain embryonic mouse cranial sensory neurons. It is the first species-specific neurotrophin to be identified and it can discriminate at high concentrati...
Experimental Neurology, 1992
We investigated the death of dorsal lateral geniculate nucleus (dLGN) neurons after lesions to the visual cortex of adult rats and the effects of supplying target-derived neurotrophic molecules to the lesion cavity. The neurotrophic factor is retrieved from cocultures of the embryonic primordia of the geniculocortieal pathway and its survival promoting properties for different populations of dLGN neurons (based on their time of origin) have been documented in previous studies of neonatal rats with occipital cortex lesions. In the present study, rats were exposed to ['Hlthymidine on El4 or E 15/16 to label either earlier or later generated dLGN neurons. When animals were at least 45 days old we made discrete lesions to the principal projection zones in area 17 of these two dLGN populations. Counts of surviving labeled cells show a relatively rapid death of E15/16 dLGN neurons in control animals, with a maximal loss by 2 weeks postlesion. The death of El4 dLGN neurons is more protracted, with a maximal loss by 2 months postlesion. A a-week infusion of the CM fraction rescues the majority of the neurons that would otherwise die in both populations compared to the controls which receive a similarly prepared fraction of unconditioned medium. Moreover, this CM fraction can sustain E14generated dLGN neurons up to 6 weeks after the neurotrophic factor(s) is no longer being supplied exogenously. Thus the rescue of axotomized adult dLGN neurons appears to be permanent, at least for the early generated population. These findings are consistent with the idea that target-derived molecules have a role in the survival of mature neurons, as they are known to have for developing neurons. Comparison of these results with those obtained in neonatal rats suggests that intrinsic differences in the neurotrophic requirements of different dLGN neuron populations that are found during development are retained in maturity. o lssz A=-den& Press, Inc.
Neuroscience, 1998
Neurotrophin-3 promotes the differentiation and supports the survival of neuroblasts derived from the neural crest in early development. Neurotrophin-3 also plays an important role in the differentiation and survival of a subpopulation of large sensory neurons after their axons arrive at their targets. Proprioception and mechanoception are lost after gene deletion of neurotrophin-3 or its high-affinity receptor, TrkC. However, the function of neurotrophin-3 during late development and in mature animals is not clear. We have used an antiserum, specific for neurotrophin-3, to neutralize endogenous neurotrophin-3 in postnatal rats to determine its role in late sensory neuron development. Administration of the antiserum for a period of two weeks, but not one week, resulted in a 20% reduction in the number of primary sensory neurons in the dorsal root ganglia and a 19% reduction in the number of myelinated axons in the saphenous nerve. The size distribution histogram also indicated that a subpopulation of large neurons was lost by the neurotrophin-3 antiserum treatment. This neuronal loss was accompanied by reduced cell soma sizes and weights of the ganglia. Immunoreactivities for calbindin and calretinin were reduced in the trigeminal and dorsal root ganglia and nerve fibres surrounding whisker hair follicles. The number of Merkel cells in touch domes labelled with quinacrine and the number of parvalbumin-immunoreactive neurons in the dorsal root ganglia were significantly reduced by the antibody treatment. In contrast, the number of muscle spindles in the gastrocnemius muscle is not reduced by the neurotrophin-3 antiserum.
Developmental Biology, 2000
Neurotrophins control neuron number during development by promoting the generation and survival of neurons and by regulating programmed neuronal death. In the latter case, the cell death induced by nerve growth factor (NGF) in the developing chick retina is mediated by p75 NTR , the common neurotrophin receptor (J. M. Frade, A. Rodriguez-Tebar, and Y.-A. Barde, 1996, Nature 383, 166-168). Here we show that NGF also induces the programmed death of paraxial mesoderm cells in the developing somites. Both NGF and p75 NTR are expressed in the somites of chick embryos at the time and the place of programmed cell death. Moreover, neutralizing the activity of endogenous NGF with a specific blocking antibody, or antagonizing NGF binding to p75 NTR by the application of human NT-4/5, reduces the levels of apoptotic cell death in both the sclerotome and the dermamyotome by about 50 and 70%, respectively. Previous data have shown that Sonic hedgehog is necessary for the survival of differentiated somite cells. Consistent with this, Sonic hedgehog induces a decrease of NGF mRNA in somite explant cultures, thus showing the antagonistic effect of NGF and Sonic hedgehog with respect to somite cell survival. The regulation of programmed cell death by NGF/p75 NTR in a mesoderm-derived tissue demonstrates the capacity of neurotrophins and their receptors to influence critical developmental processes both within and outside of the nervous system.
Neuroscience Letters, 1999
The effect of three different neurotrophins on axotomy-induced death of adult rat sensory neurons was examined. The ventral branch of the 13th spinal nerve was transected and the corresponding neurons in the 13th thoracic (T13) dorsal root ganglion (DRG) were pre-labelled with Fast Blue (FB). For a period of 4 weeks, animals received either no treatment, continuous intrathecal infusion of phosphate buffer, nerve growth factor (NGF), neurotrophin-3 (NT-3), or brain-derived neurotrophic factor (BDNF). Labelled neurons remaining after this period were counted. Inert, or no treatment, resulted in extensive loss of the DRG neurons. BDNF application was virtually non-effective, while NGF or NT-3 resulted in a greater number of FB-labelled neurons compared to normal controls. This suggests that NGF and NT-3 are survival factors for adult sensory neurons with a therapeutic potential in peripheral nerve injuries.
The Journal of Neuroscience, 2000
Schwann cells express the low-affinity neurotrophin receptor (p75), but no role for either the neurotrophins or their cognate receptors in Schwann cell development has been established. We have found that Schwann cells isolated from postnatal day 1 (P1) or P2 mice that were p75-deficient exhibited potentiated survival compared to wild-type cells after growth factor and serum withdrawal. There was, however, no disparity in the survival of p75-deficient and wild-type Schwann cells isolated at embryonic day 15, suggesting that the death-inducing effects of p75 are developmentally regulated. A comparable degree of cell death was also observed in the sciatic nerves of both wild-type and p75-deficient mice at P1. However, 24 hr after axotomy, there was a 13-fold increase in the percentage of apoptotic nuclei in the distal nerve stumps of the transected sciatic nerves of neonatal wild-type but not p75-deficient mice. The expression of both the p75 and nerve growth factor (NGF) genes was upregulated after axotomy in neonatal wild-type nerves. Collectively, these results suggest that NGF-mediated activation of p75 is likely to be an important mediator of Schwann cell apoptosis in the context of peripheral nerve injury.
Neurotrophins Require Distinct Extracellular Signals to Promote the Survival of CNS Neurons in Vitro
Experimental Neurology, 2000
Although the neurotrophins BDNF and NT-3 have been recognized as potent survival factors for distinct neuronal populations in the peripheral nervous system, they seem to have only minor effects on the survival of CNS neurons. In the present study, we provide evidence that BDNF and NT-3 require distinct additional extracellular signals in order to effectively promote the survival of several established populations of target neurons in the CNS. In dissociated cell cultures of the embryonic rat mesencephalon, BDNF promoted dopaminergic cell survival only after a delay of several days. Even after prolonged cultivation, survival promoting effects were completely absent with NT-3. Irrespective of the cultivation time, survival promoting effects of both BDNF and NT-3 on dopaminergic neurons were induced or potentiated upon simultaneous depolarization of cultured mesencephalic cells with NMDA or upon activation of cAMP/PKA-dependent signaling pathways with dibutyryl cAMP. Dibutyryl cAMP (dbcAMP), but not NMDA, also potentiated or induced the survival promoting effects of BDNF and NT-3 on cultured cerebellar granule cells. None of these substances, either alone or in combination, affected the survival of cultured cortical neurons. However, cortical cell survival increased upon depolarization with elevated potassium; an effect known to involve the induction of an autocrine BDNF loop. In both cerebellar and mesencephalic neurons, but not in cortical neurons, dbcAMP also potentiated neurotrophininduced c-fos response, indicating intimate cross-coupling of signaling pathways activated by these different factors. Together these findings suggest that in the CNS, neurotrophins preferentially promote the survival of functionally active neurons. Our findings further reveal that the neuronal response to neurotrophins is modulated in a brain region-specific manner.
Journal of Neuropathology & Experimental Neurology, 2003
Schwann cell death is a developmentally regulated phenomenon and is also induced after peripheral nerve axotomy in neonatal rodents. In this study, we explored whether ligand-induced activation of the low-affinity neurotrophin receptor (p75 NTR) is responsible for inducing Schwann cell death in vivo. Administration of exogenous nerve growth factor (NGF) to the axotomized nerve site in wild-type animals resulted in a 2.6-fold increase in Schwann cell apoptosis in the distal nerve stumps compared to axotomy alone. No increase in apoptosis, above baseline levels, was seen in p75 NTRmutant mice either with or without NGF. When anti-NGF antibodies were administered to the site of the peripheral nerve lesion in wild-type mice there was a reduction in the percentage of Schwann cell apoptosis to levels seen in both the quiescent state and in the axotomized nerves of the p75 NTR-mutant mice. These results demonstrate that apoptosis of Schwann cells in axotomized peripheral nerve is mediated predominantly through p75 NTR signaling and initiated via endogenously produced NGF.