The long term goals of this project are to gain a better understanding of the cellular and molecular mechanisms involved in the regulation of neuronal survival during development and the pathways by which neurons undergo programmed cell death (PCD). The specific studies proposed here arise from previous studies by us and others using avian embryo spinal motoneurons (MNs) as a model to examine the means by which trophic molecules and other cell-cell signals regulate survival and death both in vivo and in vitro. A unique aspect of the proposal is the use of both in vitro and in vivo models of PCD. The in vitro assay will allow us to distinguish direct vs indirect effects on MNs, whereas the in vivo model provides a means to evaluate the physiological significance of our in vitro observations.
The specific aims of this proposal are designed to address several questions regarding MN survival and death. These are as follows: l) Are there specific muscle-derived (or other) trophic agents that act to promote MN survival in vitro and in vivo and can these agents, either alone or in combination, rescue all of the MNs that undergo naturally occurring PCD? 2) Does the inhibition of endogenous sources of these putative factors by neutralizing antibodies or anti- sense methods reduce MN survival? 3) Are there specific known or novel genes and proteins that act to prevent (e.g. bcl-2) or induce (e.g ICE) the death of developing MNs? 4) Do postmitotic MNs that undergo PCD exhibit an abortive attempt to reenter the cell cycle and is this an important pathway that ultimately results in their subsequent degeneration? 5) Is the PCD of MNS associated with oxidative stress and is this an essential physiological pathway in the degradative events involved in their degeneration? These studies will help to clarify the role of specific neurotrophic agents in regulating motoneuron survival and will begin to address the issue of the role of specific genes and molecular pathways in the survival and death of developing neurons. it is also expected that these studies will result in a better understanding of the mechanisms involved in cell death during pathology and disease.
|Kim, Woon Ryoung; Chun, Sung Kun; Kim, Tae Woo et al. (2011) Evidence for the spontaneous production but massive programmed cell death of new neurons in the subcallosal zone of the postnatal mouse brain. Eur J Neurosci 33:599-611|
|Kim, Woon Ryoung; Park, Ok-Hee; Choi, Sukwoo et al. (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 29:1408-21|
|Oppenheim, Ronald W; Blomgren, Klas; Ethell, Douglas W et al. (2008) Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy. J Neurosci 28:1490-7|
|Jung, A-Rong; Kim, Tae Woo; Rhyu, Im Joo et al. (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 Neurosci 28:2941-8|
|Kim, Woon Ryoung; Kim, Younghwa; Eun, Bokkee et al. (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 Neurosci 27:14392-403|
|Park, Ok-hee; Lee, Kea Joo; Rhyu, Im Joo et al. (2007) Bax-dependent and -independent death of motoneurons after facial nerve injury in adult mice. Eur J Neurosci 26:1421-32|
|Sato, N; Sakuma, C; Sato, Y et al. (2006) Distinct susceptibility of developing neurons to death following Bax overexpression in the chicken embryo. Cell Death Differ 13:435-45|
|Winseck, Adam K; Oppenheim, Ronald W (2006) An in vivo analysis of Schwann cell programmed cell death in embryonic mice: the role of axons, glial growth factor, and the pro-apoptotic gene Bax. Eur J Neurosci 24:2105-17|
|Buss, Robert R; Gould, Thomas W; Ma, Jianjun et al. (2006) Neuromuscular development in the absence of programmed cell death: phenotypic alteration of motoneurons and muscle. J Neurosci 26:13413-27|
|Sun, Woong; Gould, Thomas W; Newbern, Jason et al. (2005) Phosphorylation of c-Jun in avian and mammalian motoneurons in vivo during programmed cell death: an early reversible event in the apoptotic cascade. J Neurosci 25:5595-603|
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