Papers by Ronald Oppenheim
The Journal of Neuroscience, Jun 15, 1996
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J Neuropathol Exp Neurol, 1996
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The neurotrophin, brain-derived neurotrophic factor, prevents motoneuron cell death during the no... more The neurotrophin, brain-derived neurotrophic factor, prevents motoneuron cell death during the normal development of the chick embryo. Brain-derived neurotrophic factor is a ligand for the low-affinity NGF receptor, p75, and for the high-affinity neurotrophin receptor, trkB. If motoneurons respond directly to brain-derived neurotrophic factor then they must possess at least one, and possibly both, of these receptors during the period of naturally occurring cell death. Histological sections from the lumbar region of chick embryos were probed for the presence of trkB and p75 mRNA using digoxigenin-labeled anti-sense RNA probes. p75 mRNA was present in spinal cord motoneurons at stages of development that correlate with motoneuron cell death. Immunohistochemical localization also revealed that p75 protein was present in motoneurons, primarily along the ventral roots and developing intramuscular nerves. In contrast trkB mRNA was not present in chick motoneurons until after the process of cell death was underway. The timing of trkB expression suggested that some motoneurons, i.e., those that die prior to the onset of trkB expression, may be insensitive to brain-derived neurotrophic factor. This was confirmed by comparing the number of surviving motoneurons following different in vivo treatment paradigms. The evidence indicates that motoneurons undergo a temporal shift in sensitivity to brain-derived neurotrophic factor.
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Journal of Comparative Neurology, 2002
Naturally occurring programmed cell death of lumbar motor neurons in the chick spinal cord occurs... more Naturally occurring programmed cell death of lumbar motor neurons in the chick spinal cord occurs between embryonic day (E) 6 and E12; whereas, a peak of motor neuron degeneration in the human spinal cord occurs between 12 and 16 weeks gestation. One of the major neurotransmitters, acetylcholine, is released from the embryonic motor neuron early in development and is thought to be responsible for early muscle activity that serves as a signal for regulating motor neuron survival. The effects of acetylcholine are mediated by two functionally distinct classes of receptors; namely, muscarinic and nicotinic with nicotinic receptors being used at the neuromuscular synapse. In this study, we determined the developmental expression profile of nicotinic acetylcholine receptor subunits in the chick and human lumbar motor neurons and skeletal muscle using reverse transcription polymerase chain reaction, immunoblots, and immunocytochemistry. Our results show that, in the chick, nicotinic receptor subunits alpha1, alpha4, alpha7, alpha8, and beta2 appear to be regulated during the process of naturally occurring motor neuron cell death in the spinal cord. A new finding was the expression of alpha8 mRNA and protein from E4.5 through E7 in chick motor neurons. Interestingly, we also found that, at E14, alpha8 protein was localized only in sensory dorsal horn neurons. In the developing human spinal cord, we determined that nicotinic receptor subunits alpha1, alpha2, alpha3, alpha4, alpha7, beta2, and beta3 were expressed before the programmed cell death period, and alpha2, alpha4, alpha7, beta2, beta3, and beta4 were expressed during the programmed cell death period. Our data demonstrate that neuronal and muscle nicotinic receptor mRNAs and proteins are expressed during important embryonic periods. This finding raises the possibility that nicotinic receptors play an important role in the spinal cord and skeletal muscle during early development.
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Treatment of chick embryos in ovo with crude and partially purified extracts from embryonic hindl... more Treatment of chick embryos in ovo with crude and partially purified extracts from embryonic hindlimbs (days 8 to 9) during the normal cell death period (days 5 to 10) rescues a significant number of motoneurons from degeneration. The survival activity of partially purified extract was dose-dependent and developmentally regulated. The survival of sensory, sympathetic, parasympathetic, and a population of cholinergic sympathetic preganglionic neurons was unaffected by treatment with hindlimb extract. The massive motoneuron death that occurs after early target (hindlimb) removal was partially ameliorated by daily treatment with the hindlimb extract. These results indicate that a target-derived neurotrophic factor is involved in the regulation of motoneuron survival in vivo.
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Science, 1991
During development of the nervous system, neurons in many regions are overproduced by proliferati... more During development of the nervous system, neurons in many regions are overproduced by proliferation, after which the excess cells are eliminated by cell death. The survival of only a proportion of neurons during normal development is thought to be regulated by the limited availability of neurotrophic agents. One such putative trophic agent is ciliary neurotrophic factor (CNTF), a polypeptide that promotes the survival of ciliary, sensory, and sympathetic neurons in vitro. In contrast to the results of in vitro studies, however, the daily treatment of chick embryos in vivo with purified human recombinant CNTF failed to rescue any of these cell populations from cell death, whereas CNTF did promote the in vivo survival of spinal motoneurons. Thus, CNTF may not act as a neurotrophic agent in vivo for those embryonic neurons (especially ciliary neurons) on which it acts in vitro. Rather, CNTF may be required for in vivo survival of motoneurons.
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The Journal of Neuroscience the Official Journal of the Society For Neuroscience, 2000
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Nature, 1985
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J Neurobiol, 1994
During normal development, large numbers of neurons die by programmed cell death. This phenomena ... more During normal development, large numbers of neurons die by programmed cell death. This phenomena has been extensively studied in the lateral motor column of chick embryos, where approximately 50% of the motoneurons that are initially produced, subsequently die due in part to competition for a limited supply of target-derived trophic support. Inhibitors of RNA and protein synthesis block this cell loss in vivo, indicating a requirement for new gene expression (Oppenheim et al., 1990). Prior to their commitment to death, motoneurons can be isolated as a relatively pure population from chick spinal cord for in vitro study. Cells plated with muscle extract, a potent source of target-derived trophic support, survive, and have large, phase-bright cell bodies and extensive neurite outgrowth. In contrast, motoneurons cultured in the absence of muscle extract die within 48 h. This death can be blocked by the RNA synthesis inhibitor actinomycin D, at the time when the cells become committed to die, suggesting that new gene expression is required for cell death. DNA fragmentation and nuclear condensation indicate that some of these cells die by apoptosis. Therefore, it appears that many aspects of motoneuron development observed in vivo can be reconstituted in vitro. These cultures can be used as a model system for studying neuronal death and may contribute to an understanding of the molecular mechanisms that mediate programmed cell death during neuronal development.
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Advances in Neurology, Feb 1, 1997
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Cell and Tissue Research, Dec 1, 1996
During normal development of many vertebrate species, substantial numbers of neurons in the centr... more During normal development of many vertebrate species, substantial numbers of neurons in the central and peripheral nervous system undergo naturally occurring (or programmed) cell death. For example, approximately 50% of spinal motoneurons degenerate and die at a time when these cells are establishing synaptic connections with their target muscles in the chick, mouse, rat, and human. It is generally thought that the survival of developing motoneurons depends on access to trophic molecules. Motoneurons that survive the period of programmed cell death may also die following injury in the developing or adult animal. Increasing evidence suggests that glial-cell-line-derived neurotrophic factor (GDNF) plays a physiological and/or pharmacological role in the survival of various neuronal cell types, including motoneurons. In this paper, we review the survival and growth-promoting effects of GDNF on spinal motoneurons during the period of programmed cell death and following injury.
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Development, Feb 1, 1991
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Method Cell Biol, 1995
The study of neuronal death involves demonstrating that it occurs in a given situation, estimatin... more The study of neuronal death involves demonstrating that it occurs in a given situation, estimating the magnitude and timing of the loss, evaluating which particular neurons die, analyzing why and how they die, and understanding the role or purpose of the loss. A wide range of methods is available for achieving these ends; most involve the use of histological sections, although biochemical analysis of homogenized tissue can also provide useful information. Counting healthy neurons in histological sections is the most direct and widely used method for estimating the number of neurons that die, and the timing of their loss. Because most cases of neuronal death occur in postmitotic populations, there is rarely any need to consider complex tissue kinetics; the number of neurons lost is simply the initial number minus the final number in a defined population. However, the fact that subtraction is used makes the final estimation of neuronal death highly sensitive to errors in the estimations of total neuronal number. To meet the high standards of accuracy that are required in counting healthy neurons, it is essential to avoid two main sources of error: those because of inadequate definition of the population to be counted and those in counting.
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Nature, 1978
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Journal of Comparative and Physiological Psychology, 1970
Destroyed selectively parts of the avian embryonic nervous system by ionizing radiation and evalu... more Destroyed selectively parts of the avian embryonic nervous system by ionizing radiation and evaluated the possible behavioral effects of this destruction. Accordingly, duck and chick embryos were irradiated at different stages of development with varying doses of gamma rays (200, 400, 700, 1000 r.). Subsequently, embryonic behavior, hatching behavior, posthatching approach behavior, and posthatching color preferences were evaluated. Except for a reliable difference in time of hatching (irradiated embryos hatched 6-8 hr. later than controls), there were no consistent differences between irradiated and control embryos on any of the measures. Counts of sensory and motor cells in the spinal cord also revealed no differences between control and irradiated embryos. Results indicate that the nervous system of bird embryos is less susceptible to ionizing radiation than the developing mammalian nervous system. (32 ref.)
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The Journal of Neuroscience, 1991
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The Journal of Neuroscience, Dec 15, 1999
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Papers by Ronald Oppenheim