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The role of c-Jun N-terminal kinase one and two in motoneuron maturation and maintenance

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The role of c-Jun N-terminal kinase one and two in motoneuron maturation and maintenance
Hayes, Crystal Dawn
During development motoneurons (MNs) undergo programmed cell death (PCD), and the molecular coordination of intracellular signaling and death execution pathways are prominent areas of research (Hamburger, 1958; Hollyday and Hamburger, 1976; Oppenheim, 1991; Oppenheim., 2005 ). Subgroups of the mitogen activated protein kinases (MAPK) family have been implicated in neuronal differentiation, death, regeneration, and survival (Bogoyevitch and Kobe, 2006; Frebel and Wiese, 2006). The c-Jun N-terminal kinases (JNKs) are stress-activated members of the MAPK family, which may represent candidate molecules whose signaling is important in MN death, survival, differentiation, maturation, and maintenance. Classically considered a degenerative signal, JNK may be critical for MN survival and death throughout life; though the outcome of its activation varies depending upon the isoform, location, and context (Ip and Davis, 1998; Bogoyevitch and Kobe, 2006). Previous work from our laboratory has provided evidence that cytosolic, nuclear, and mitochondrial pools of JNK activity may regulate both degenerative and regenerative events in vitro. Inhibition of JNK in healthy MNs results in decreased mitochondrial membrane potential, neurite outgrowth, and phosphorylation of MAP1B, demonstrating that the activation of JNK is necessary for normal maintenance of the MN. In contrast, JNK inhibition in MNs deprived of trophic support attenuates caspase activity and nuclear condensation, expounding on the role of JNK activation in cell death. Together, these data implicate a dual function of JNK in MNs in vitro (Newbern et al., 2007). Further isoform-specific investigation in an in vivo model is necessary to elucidate the role of the JNK isoforms in lumbar MNs. In the mammalian genome, three genes code for the JNK isoforms: JNK1, JNK2, and JNK3 with ten splice variants. In this dissertation, the transgenic jnk1 or jnk2 mouse models were utilized to characterize the functions of JNK1 or JNK2 in lumbar MNs in vivo. We hypothesize that the JNK1 and JNK2 isoform mediate discrete events associated with MN maturation and maintenance. These data suggest that the JNK1 or JNK2 isoform have a minimal role in the development of MNs. There were decreases in the interaction of the MN with their target muscles in JNK1 or JNK2 KO animals. Therefore, the individual JNK isoforms appear to have limited, but specific roles in lumbar MNs in vivo. Alternatively, the function of the JNK1 or JNK2 isoform may not be entirely obvious when the remaining isoforms are fully expressed, due to compensatory regulation (Sabapathy et al., 1999a; Tuncman et al., 2006). Additional experiments utilizing the double transgenic JNK1KO/JNK2HT, JNK1HT/JNK2KO, or JNK1HT/JNK2HT mouse models might further illuminate the role of the specific JNK isoforms in MNs.
Milligan, Carolanne E (committee chair)
Oppenheim, Ronald W (committee member)
Riddle, David R (committee member)
Smith, Thomas (committee member)
2011-02-16T21:42:25Z (accessioned)
2011-10-11T08:30:12Z (available)
2010 (issued)
Neurobiology & Anatomy (discipline)
2011-10-11 (terms)
http://hdl.handle.net/10339/30409 (uri)
en (iso)
Wake Forest University

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