Ronald W. Oppenheim, PhD
Washington University, St. Louis, 1968
Development of nervous system; programmed cell death; behavioral development; neurodegenerative disease; synaptogenesis; neural activity and brain development; history of neuroscience.
The development of a complex, multi-cellular animal from a single cell, the fertilized egg, is one of the most miraculous, intriguing and least understood events in biology. Shortly after fertilization the embryo begins to grow and develop rapidly by the gradual attainment of new cells, tissues, organs and functions. This progressive construction of new parts and functions is generally considered to be the hallmark of development. Yet beneath the surface of this biological construction process, seemingly insidious forces are at work which if unchecked could undermine the major goal of development. That is, while at one level of analysis constructive, progressive forces are gradually building the tissues and organs of the embryonic body, at other levels (cellular, molecular) non-pathological destructive and regressive events are occurring. Although these regressive events can take a number of different forms and may involve different cellular and molecular events, the most dramatic and devastating of these is cell death.
In many different tissues and organs in the developing embryo, including the nervous system, massive numbers of differentiating cells degenerate and die. In some parts of the nervous system the cells that die may even outnumber those that survive. Because embryonic cell death is highly stereotyped in space and time and because it occurs to same extent in all individual members of a species, one can conclude that it is neither a random nor pathological process. By focusing on specific populations of neurons, we have been attempting to force the embryo to reveal its secrets regarding the mechanisms and significance of naturally occurring neuronal death.
Previous studies have shown that the formation of early connections with targets and afferents plays an important role in regulating neuronal survival. The specific signals that mediate these target and afferent influences are of considerable interest. Recent studies suggest that synaptic transmission, post-synaptic activity, axonal branching and terminal contacts, and secreted neurotrophic molecules may all be used as signals to regulate the number of surviving neurons. We are attempting to understand the cellular and molecular events involved in each of these suspected regulatory processes. Attainment of this goal may help shed light on the reasons why neurons die pathologically later in life, as occurs in a variety of human neurodegenerative disorders, and may also aid in understanding the biological significance of this intriguing but still poorly understood phenomenon.
Neuronal death is only one of many critical steps in the construction of a nervous system. The attainment of appropriate connections between neurons and their targets is another fundamental event that is of great interest to developmental neuroscientists. The emergence of adaptively appropriate behavioral patterns depends upon the formation of organized patterns of connectivity. We have been studying the formation of axonal pathways and synaptic connections by spinal cord neurons in the chick embryo that project within the central nervous system to spinal and brain targets. Our initial studies indicate that the pathways formed by the axons of these cells project unerringly in the appropriate locations and directions from the very onset of pathway formation. We are presently using in ovo and in vitro preparations for carrying out a variety of surgical, pharmacological and immunological perturbations to reveal the cellular, extracellular and molecular cues involved in pathway formation. Because the pathways involved here are used early in development for mediating pre- and post-natal behavior, these studies may also reveal important principles of early neurobehavioral development.
Kim WR, Kim Y, Eun B, Park O, Kim H, Kim K, Park C-H, Vinsant S, Oppenheim RW, and Sun W 2007 Impaired migration in the rostral migratory stream but spared olfactory function after the elimination of programmed cell death in Bax knock-out mice. J Neuroscience 27(52): 14392-14403.
Oppenheim RW, Blomgren K, Ethell DW, Koike M, Komatsu M, Prevette D, Roth KA, Uchiyama Y, Vinsant S, and Zhu C 2008 Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-Independent, nonapoptotic pathway involving autophagy. J Neuroscience 28(6):1490-1497.
Gould TW, Yonemura S, Oppenheim RW, Ohmori S, and Enomoto H 2008 The neurotrophic effects of glial cell line-derived neurotrophic factor on spinal motoneurons are restricted to fusimotor subtypes. J Neuroscience 28(9): 2131-2146.
Jung A, Kim TW, Rhyu IJ, Kim H, Lee YD, Vinsant S, Oppenheim RW, and Sun W 2008 Misplacement of Purkinje cells during postnatal development in Bax knock-out mice: A novel role for programmed cell death in the nervous system. J Neuroscience 28(11): 2941-2948.
Oppenheim RW, Calderó J, Cuitat D, Esquerda J, McArdle JJ, Olivera BM, Prevette D, Teichert RW 2008 The rescue of developing avian motoneurons from programmed cell death by a selective inhibitor of the fetal muscle-specific nicotinic acetylcholine receptor. Develop Neurobiol 68: 972-980.
Kim WR, Park O, Choi S, Choi S-Y, Park SK, Lee KJ, Rhyu IJ, Kim H, Lee YK, Kim HT, Oppenheim RW, and Sun W 2009 The maintenance of specific aspects of neuronal function and behavior is dependent on programmed cell death of adult-generated neurons in the dentate gyrus. Eur J Neurosci 29: 1408-1421.