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The X-Linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain

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The X-Linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain The X-linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Zhang, Chi. 2013. The X-linked Intellectual Disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11156785 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA © 2013- Chi Zhang All rights reserved. Dissertation Advisor: Professor Azad Bonni Chi Zhang The X-linked Intellectual disability Protein PHF6 Associates with the PAF1 Complex and Regulates Neuronal Migration in the Mammalian Brain Abstract Intellectual disability is a prevalent developmental disorder for which no effective treatments are available. Mutations of the X-linked protein PHF6 cause the Börjeson– Forssman–Lehmann syndrome (BFLS) that is characterized by intellectual disability and epilepsy. However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. Here, I present my dissertation research demonstrating that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo, leading to the formation of white matter heterotopias that harbor aberrant patterns of neuronal activity. Importantly, BFLS patient specific mutation of PHF6 blocks its ability to promote neuronal migration. I also elucidate the mechanism by which PHF6 drives neuronal migration in the cerebral cortex. PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. I further identify Neuroglycan C (NGC), a susceptibility gene for schizophrenia, as a critical downstream target of PHF6 and the PAF1 complex, and I demonstrate that NGC mediates PHF6-dependent neuronal migration. These findings define PHF6, the PAF1 transcription elongation complex, and NGC as components of a novel cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of intellectual disability and potentially other neuropsychiatric disorders. iii Table of Contents Introduction ......................................................................................................................... 1 Intellectual disability is a prevalent disorder................................................................... 2 Development of the cerebral cortex ................................................................................ 6 Transcriptional regulation of neuronal migration ......................................................... 10 PHF6 plays an essential role in radial neuronal migration in the cerebral cortex in vivo 12 Introduction ................................................................................................................... 13 Results ........................................................................................................................... 15 Discussion ..................................................................................................................... 37 Methods ......................................................................................................................... 39 The PAF1 complex interacts with PHF6 and plays a critical role in radial migration of neurons in the cerebral cortex in vivo ............................................................................... 43 Introduction ................................................................................................................... 44 Results ........................................................................................................................... 46 Discussion ..................................................................................................................... 54 Methods ......................................................................................................................... 56 The Neuroglycan C (NGC) gene is a key downstream target of PHF6 and PAF1 in the control of neuronal migration in vivo ............................................................................... 59 Introduction ................................................................................................................... 60 Results ........................................................................................................................... 61 Discussion ..................................................................................................................... 70 Methods ......................................................................................................................... 72 PHF6 knockdown triggers the formation of white matter heterotopias with aberrant neuronal activity................................................................................................................ 74 Introduction ................................................................................................................... 75 Results ........................................................................................................................... 77 Discussion ..................................................................................................................... 83 Methods ......................................................................................................................... 86 Perspectives....................................................................................................................... 88 Important role of transcriptional elongation in neuronal development ......................... 89 iv What is the biochemical function of PHF6 ................................................................... 92 Implications on cancer biology ..................................................................................... 94 Functional consequence of ectopic neuronal activity on brain function ....................... 95 Appendix ........................................................................................................................... 97 PHF6 is a potential substrate for the protein kinase Cdk5 ............................................ 98 PHF6 might control additional stages of neuronal maturation ................................... 103 FoxA family members are potential substrates for MST1, a protein kinase involved in apoptosis signaling ...................................................................................................... 109 Unbiased screen to search for MST1 consensus phosphorylation site........................ 113 FoxA1 RNAi leads to altered Golgi and centrosomal location in cerebellar granule neurons ........................................................................................................................ 116 References ....................................................................................................................... 124 v Acknowledgements I would like to thank my thesis adviser, Dr. Azad Bonni, for his support and mentorship throughout my graduate career. He supported the project all the way from the beginning, and allowed me to explore new directions. With his help and support I was able to carry out interesting projects. In addition, his mentorship, both scientific and personal, helped me grow into a mature scientist. As an insightful scientist, he always asks good questions that will lead to new directions or surprising findings in the project. As a mentor, he is always available and approachable for questions and concerns. His passion and dedication for his work are great stimulating forces that push me to perform my best. No less importantly, he assembled a team of great postdocs and graduate students, from whom I learnt tremendously. I truly appreciate his support and guidance throughout my graduate school career. I would like to thank my colleagues in the lab who have helped me along the way, including Tomoko Yamada, Yoshiho Ikeuchi, Gilbert Gallardo, Arezu Jahani-Asl, Luis de la Torre, Yue Yang, Parizad M. Bilimoria, Mai Anh Huynh, Nadia Litterman, Sidharth Puram, Luis Mejía, Julius Anckar, Pamela Valnegri, Ju Huang, Celine Vuong, Zengqiang Yuan and Jessica Barowski. I’ve spent an unforgettable 6 years with everyone and I truly enjoyed the time here. I also learned tremendously from all members of the lab and I really appreciate their help. I would like to thank my dissertation advisory committee members Xi He, John Flanagan, and Andrew Lassar for sharing with me their advice on my science and my career. Their vi knowledge and enthusiasm really helped me go through the difficult times of my graduate career. I would like to thank Bjorn Olsen, my director in the graduate program, for taking me into the program, and more importantly, always supporting me and backing me up whenever I get into trouble. I truly enjoyed meeting and talking to Bjorn and take him as one of my closest friends here in Harvard. Finally, I would like to thank my family, including my parents Baolin Zhang and Lihong Liu, my past grandfather
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