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Identification and characterization of Actb mRNA localization factors in the nervous system

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dc.contributor.advisor Czaplinski, Kevin en_US
dc.contributor.advisor Talmage, David en_US
dc.contributor.author Sinnamon, John Richard en_US
dc.contributor.other Department of Neuroscience. en_US
dc.date.accessioned 2017-09-20T16:50:42Z
dc.date.available 2017-09-20T16:50:42Z
dc.date.issued 2015-08-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76587 en_US
dc.description 135 pg. en_US
dc.description.abstract Abstract The local translation of trafficked mRNAs temporally and spatially regulates protein expression. In neurons, mRNAs are trafficked to both axons and dendrites and the local translation of these mRNAs is important for axon guidance as well as synaptic plasticity. The active trafficking of mRNAs involves the interaction between cis¬¬-acting localization elements, known as `zipcodes,' and trans-acting factors, including RNA-binding proteins. However, the exact molecular mechanism of mRNA localization in the mammalian nervous system remains unknown. To better understand this process, the zipcode element of  -actin (Actb) mRNA was used to identify putative  -actin zipcode binding proteins from the rodent brain (bZBPs). Hnrnpab was confirmed as a bZBP and was found to have an unexpected isoform dependent specificity. The larger isoform, Hnrnpab1, is specific for Actb mRNA and the zipcode localization element. The alternatively spliced isoform, Hnrnpab2, interacts with the zipcode element and the 5' UTR of Actb mRNA as well as  -actin (Actg) mRNA. Analysis using a novel fluorescent in situ hybridization method demonstrated a decrease in Actb mRNA in the periphery of cells in the absence of Hnrnpab. This effect can be rescued only with the Hnrnpab1 isoform, suggesting a distinct function in Actb mRNA localization. Mice lacking Hnrnpab show a number of changes in protein expression which suggest a role in nervous system development and glutamate signaling. Hnrnpab-/- neural stem and progenitor cells undergo altered differentiation patterns in culture, and mature Hnrnpab-/- neurons demonstrate increased sensitivity to glutamate-induced excitotoxicity. These studies represent an important step in understanding the underlying molecular mechanism of mRNA trafficking by identifying several putative localization factors using the localization element of Actb mRNA and establishing Hnrnpab1 as a zipcode binding protein, which mediates Actb mRNA localization. They also explore the role of Hnrnpab in the nervous system and provide evidence for isoform dependent functions. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biology en_US
dc.title Identification and characterization of Actb mRNA localization factors in the nervous system en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Halegoua, Simon en_US
dc.contributor.committeemember Twiss, Jeffery. en_US

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