Understanding of the regulatory pathways which operate on the nervous system will be crucial to prevention and cure of neuronal disorders. Organization of cytoskeletal elements is critical for neuron migration and axon formation. Tau protein, which binds to and organizes microtubules, is instrumental in establishing neuron morphology. The neuron-specific tau transcript gives rise to multiple isoforms via developmental stage- and tissue-specific alternative splicing. Disturbances in tau splicing result in disruption of the neuronal cytoskeleton and formation of pathological tau structures (neurofibrillary tangles) found in brains of dementia sufferers. The objective of this proposal is to investigate the mechanisms that underlie the alternative splicing of regions of the human tau gene as well as the function of the domains encoded by these regions. Specifically, this study aims to explore the splicing regulation and function of tau alternative exons by the following methods: 1) Sequencing of the tau gene cloned segments that contain the alternatively spliced exons and establishment of utilization of these exons in fetal and adult human brain and in human neuroblastoma cells. 2) Construction of minigene constructs that contain the tau alternatively spliced exons and examination of their behavior in neuroblastoma and non-neuronal cells. Cis elements that play a role in alternative processing of the tau gene will be determined by deletions of introns and/or exons included in the original minigenes and investigation of their transcripts in vivo and in vitro. 3) Identification of trans factors that are involved in splicing of the tau optional exons by complementation of the generic in vitro splicing extract with either extracts from neuroblastoma cells or already characterized splicing factors. 4) Identification and characterization of cellular factors which interact with the domains encoded by the alternative tau exons by use of the yeast two-hybrid system. cDNA brain libraries will be examined for binding to target plasmids bearing the tau alternative exons. The tissue specificity and developmental profile of novel proteins identified by this method will be investigated as a preliminary step to characterizing their encoding genes. The physiological relevance of the interaction will be validated by in vivo or in vitro binding or co-precipitation assays. Results from this work will contribute to the understanding of neuronal plasticity and specialization during development. Long term, this research will grant insights into the neurogenic cascade and hence into abnormal processes common to Down syndrome and Alzheimer's disease.

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Eunice Kennedy Shriver Center Mtl Retardatn
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