The major goal of this application is to examine the cellular and molecular mechanisms that mediate activity-dependent motoneuron survival during development in avian (chick) and mammalian (mouse) embryos. Chronic activity blockade during the period of naturally occurring motoneuron death promotes motoneuron survival. Previous studies are supportive of the hypothesis that neuromuscular activity in the embryo modulates intramuscular axon branching which in turn provides access of motoneurons to muscle- derived neurotrophic factors via uptake and retrograde transport of these factors by axonal branches/terminals. An alternataive explanation is that activity regulates the production (synthesis or release) of target muscle-derived neurotrophic factors (e.g., loss of activity increases production resulting in the rescue of motoneurons). A third novel hypothesis proposes that activity blockade rescues motoneruons by a neurotrophic factor independent pathway.
Three specific aims are proposed to examine each of these alternative (but not necessarily mutually exclusive) explanations of activity-dependent MN survival. In the first aim, neurotrophic factor expression (mRNA, protein) will be assayed in muscles and nerves following in vivo perturbations of activity. In the secondaim, the role of cell adhesion molecule-mediated changes in intramuscular axon branching following perburbations of activity will be examined. In the third aim, intracellular second messenger signaling pathways will be examined in an attempt to determine whether distinct molecular mechanisms are involved in motoneuron survival mediated by neurotorphic factros ys following perturbations of activity. Collectively, the proposed studies provide novel approaches for elucidating the mechanisms involved in activity-dependent motoneuron survival in vivo, that will advance our understanding of developmental neuronal death. They also have the potential to expand our conceptualization of pathological motoneuron death by revealing ways in which alterations in neuromuscular activity may be a contributing factor in neurodegenerative diseases such as amyuotrophic lateral sclerosis (ALS) and spinal muscular atropohy (SMA).
|Taylor, Anna R; Gifondorwa, David J; Robinson, Mac B et al. (2012) Motoneuron programmed cell death in response to proBDNF. Dev Neurobiol 72:699-712|
|Suzuki, Hiromichi; Aoyama, Youhei; Senzaki, Kouji et al. (2010) Characterization of sensory neurons in the dorsal root ganglia of Bax-deficient mice. Brain Res 1362:23-31|
|Liu, Yun; Oppenheim, Ronald W; Sugiura, Yoshie et al. (2009) Abnormal development of the neuromuscular junction in Nedd4-deficient mice. Dev Biol 330:153-66|
|de Castro, Braulio M; De Jaeger, Xavier; Martins-Silva, Cristina et al. (2009) The vesicular acetylcholine transporter is required for neuromuscular development and function. Mol Cell Biol 29:5238-50|
|Oppenheim, Ronald W; Caldero, Jordi; Cuitat, Doloros et al. (2008) The rescue of developing avian motoneurons from programmed cell death by a selective inhibitor of the fetal muscle-specific nicotinic acetylcholine receptor. Dev Neurobiol 68:972-80|
|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|
|Brunet, Nuria; Tarabal, Olga; Portero-Otin, Manel et al. (2007) Survival and death of mature avian motoneurons in organotypic slice culture: trophic requirements for survival and different types of degeneration. J Comp Neurol 501:669-90|
|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|