Recent studies have shown that overexpresion of a NF transgene causes motoneuron degeneration in transgenic mice and that overexpression of endogenous NF genes preceeds the spontaneous motoneuron degeneration in Wobbler mice. The findings suggest that pathways regulating levels of NF expression are instrumental in maintaining neuronal homeostasis and that alterations in these pathways are associated with loss of homeostasis in motoneurons. Studies in this laboratory have probed the molecular basis of NF gene expression. During the past grant period, major discoveries have shown that levels of NF gene expression are regulated by steady-state levels of mRNA and that the latter are controlled by regulating the stability/instability of NF mRNA. Determinants of mRNA stability have been localized to the 3'UTR in the NF-L gene. Model systems have been developed that will allow the underlying regulatory components to be probed and identified. The proposed studies will identify the regions in each of the three NF mRNAs that regulate stabilities of the NF transcripts. Biochemical studies will be used to identify, isolate, characterize and, eventually, clone the cognate RNA binding factors. Attention will be directed at how NF mRNA binding factor interact in pathways that maintain neuronal homeostasis and how alterations in the binding factors or their levels of expression could lead to a loss of neuronal homeostasis, especially that of large, NF-rich motoneurons in the mouse.
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