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The RNA Binding Protein KSRP Destabilizes GAP-43 Mrna to Limit Axonal Elongation in Cultured Hippocampal Neurons Clark Bird

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The RNA Binding Protein KSRP Destabilizes GAP-43 Mrna to Limit Axonal Elongation in Cultured Hippocampal Neurons Clark Bird University of New Mexico UNM Digital Repository Biomedical Sciences ETDs Electronic Theses and Dissertations 12-1-2012 The RNA binding protein KSRP destabilizes GAP-43 mRNA to limit axonal elongation in cultured hippocampal neurons Clark Bird Follow this and additional works at: https://digitalrepository.unm.edu/biom_etds Recommended Citation Bird, Clark. "The RNA binding protein KSRP destabilizes GAP-43 mRNA to limit axonal elongation in cultured hippocampal neurons." (2012). https://digitalrepository.unm.edu/biom_etds/65 This Dissertation is brought to you for free and open access by the Electronic Theses and Dissertations at UNM Digital Repository. It has been accepted for inclusion in Biomedical Sciences ETDs by an authorized administrator of UNM Digital Repository. For more information, please contact [email protected]. i The RNA binding protein KSRP destabilizes GAP-43 mRNA to limit axonal elongation in cultured hippocampal neurons By Clark W. Bird B.A., Molecular, Cellular, and Developmental Biology and Psychology University of Colorado at Boulder, 2005 DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Biomedical Sciences The University of New Mexico Albuquerque, New Mexico December 2012 ii Acknowledgements None of the work contained within this dissertation would have been possible without the knowledge and patience of my mentor, Nora Perrone-Bizzozero. Her enthusiasm for science and encyclopedic knowledge of all things related to molecular biology and neuroscience were invaluable to my laboratory experience. I couldn’t have asked for a better mentor. I would like to thank all members of my dissertation committee for their valuable input and help during the last five years. Fernando Valenzuela and Kevin Caldwell were awesome rotation mentors and great teachers. Rebecca Hartley and her RNA journal club were very helpful in getting me interested in the biology of RNA, and was a fantastic teacher to boot. Their friendly faces, attitudes, and knowledge were extremely helpful to getting through my dissertation research. I also would like to thank Xinyu Zhao, a former member of my committee, for her assistance during my first few years at UNM. The members of the Perrone-Bizzozero lab, both past and present, also deserve a measure of gratitude. Sayuri Nixon in particular was a fantastic lab manager, and made performing experiments an easy process, as the lab was wonderfully organized and protocols were easy to understand. The knowledge and experience of post-doc Amy Gardiner provided a great laboratory resource. Joanna Mounce was a great lab-mate, and didn’t complain when I played terrible rock and roll around the clock. All these people made going to work every day a more pleasurable experience. The most important person I need to thank is my mother, Mary Bird. Without her none of this would have been possible, as she raised me to be an ambitious, well- mannered, sarcastic member of society. She “gently” pushed me into being more than just a sandwich shop manager and restaurant waiter. I can’t thank her enough for being there for me whenever I needed her. My girlfriend, Lindsay Rogash, has also been wonderful during my graduate experience. Dealing with a stressed-out graduate student can’t be the easiest thing in the world, and she has always been encouraging, and is great motivation to do well and be a better person. Lastly, I have to thank my cats: Dale, Eddie, and Floofball, constant companions who lifted my spirits when I needed it. iii The RNA binding protein KSRP destabilizes GAP-43 mRNA to limit axonal elongation in cultured hippocampal neurons By Clark W. Bird B.A., Molecular, Cellular and Developmental Biology and Psychology University of Colorado at Boulder Abstract The KH-type splicing regulatory protein (KSRP) promotes the decay of AU-rich element (ARE) containing mRNAs. Although KSRP is expressed in the developing and mature nervous system, very little is known about its role in regulating gene expression in the brain. In this study, we utilized in vitro binding and decay studies to examine whether KSRP regulates the stability of the GAP-43 transcript, an ARE-containing neuronal mRNA whose protein product plays a role in axonal growth and synaptic plasticity. We found KSRP destabilizes GAP-43 mRNA by binding to the GAP-43 ARE, iv a process that depends on the presence of the fourth KH domain in the protein. Furthermore, KSRP competed with another GAP-43 mRNA binding protein, the stabilizing factor HuD, for binding to these ARE sequences. Given that GAP-43 expression is crucial for accurate axonal outgrowth during neuronal development, we also examined the functional consequences of KSRP overexpression and depletion on the axonal outgrowth from primary hippocampal neurons. Overexpression of either full length KSRP or KSRP without the nuclear localization signal hindered axonal outgrowth in these cultures, while overexpression of a mutant protein without the KH4 domain did not have any effect. In contrast, depletion of KSRP led to a dramatic increase in axonal length. Concurrent overexpression of GAP-43 and KSRP rescued the axonal outgrowth deficits seen with KSRP overexpression, but only when the GAP-43 mRNA was targeted to axons using GAP-43 or amphoterin 3’ UTR sequences. Together, our results suggest that KSRP is an important regulator of GAP-43 mRNA stability and neuronal differentiation that works in direct opposition to HuD. v Table of Contents Acknowledgements .......................................................................................................... iii Abstract ............................................................................................................................. iv List of Figures ................................................................................................................. viii 1. Introduction ................................................................................................................... 1 1.1 The AU rich element and associated proteins ........................................................................................... 1 1.2 GAP-43 and HuD ...................................................................................................................................... 6 1.3 KSRP ......................................................................................................................................................... 9 1.4 Summary ................................................................................................................................................. 13 2. Rationale, hypothesis, and specific aims ................................................................... 14 2.1 Rationale.................................................................................................................................................. 14 2.2 Hypothesis ............................................................................................................................................... 14 2.3 Specific aims ........................................................................................................................................... 14 2.3.1 Specific aim 1: ...................................................................................................................................... 14 2.3.2 Specific aim 2: ...................................................................................................................................... 15 3. Regulation of GAP-43 stability by KSRP in vitro .................................................... 16 3.1 Introduction ............................................................................................................................................. 16 3.2 Materials and methods ............................................................................................................................. 17 3.3 Results ..................................................................................................................................................... 19 3.3.1 KSRP binds to GAP-43 mRNA in vitro: RNA electrophoretic mobility shift ..................................... 19 3.3.2 KSRP binds to GAP-43 mRNA in vitro: biotinylated GAP-43 mRNA pulldown (Experiment performed by Dan Tanner) .............................................................................................................. 21 3.3.3 HuD and KSRP compete for binding to the GAP-43 ARE .................................................................. 21 3.3.4 KSRP destabilizes GAP-43 mRNA in vitro ......................................................................................... 22 3.4 Discussion ............................................................................................................................................... 24 4. KSRP inhibits axonal outgrowth in cultured hippocampal neurons ..................... 26 4.1 Introduction ............................................................................................................................................. 26 4.2 Materials and methods ............................................................................................................................. 27 4.3 Results ..................................................................................................................................................... 31 4.3.1 KSRP and HuD localize to separate cytoplasmic granules in developing
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