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Identification of Apoptosis Pathway in Treacher Collins Syndrome Khaled Alsayegh Virginia Commonwealth University

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Identification of Apoptosis Pathway in Treacher Collins Syndrome Khaled Alsayegh Virginia Commonwealth University Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2009 Identification of apoptosis pathway in Treacher Collins Syndrome khaled alsayegh Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Genetics Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1859 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Virginia Commonwealth University School of Medicine This is to certify that the Thesis prepared by Khaled AlSayegh entitled IDENTIFICATION OF APOPTOSIS PATHWAY IN TREACHER COLLINS SYNDROME has been approved by his or her committee as satisfactory completion of the thesis or dissertation requirement for the degree of Master of Science Rita Shiang, Ph.D., Director of Thesis James A. Lister, Ph.D., School of Medicine Andrew Yeudall, PhD., School of Dentistry Paul B. Fisher, MPh, Ph.D., Department Chairman Jerome F. Strauss, III, M.D., Ph.D., Dean of School of Medicine DR. F. DOUGLAS BOUDINOT, DEAN OF THE SCHOOL OF GRADUATE STUDIES Date: ii © Khaled Alsayegh 2009 All Rights Reserved iii IDENTIFICATION OF APOPTOSIS PATHWAY IN TREACHER COLLINS SYNDROME A Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by KHALED AL-SAYEGH B.S, King Abdul Aziz University, Saudi Arabia, 2005 Director: DR. RITA SHIANG ASSOCIATE PROFESSOR, HUMAN MOLECULAR GENETICS Virginia Commonwealth University Richmond, Virginia 2009 1 Acknowledgement I would like to express my extreme gratuity to God, who made me able to overcome every obstacle I faced and made this journey enjoyable. I would like to thank my advisor, Dr. Rita Shiang, who has extensively shown me support and encouragement. Her guidance and advices always kept me on the right path and helped me in my career and in personal life. I would like to thank my co-advisor, Dr. James Lister, who was always patient with me and showed me continuous support. I thank Dr. Andrew Yeudall for willing to be on my committee and for being ready to answer all my questions. And last but definitely not least, I would like to thank my labmates, Sami Amr, Belal Azab, Dr.Kate Shows, Divya Vinjamur, Leyla Peachy and Brandon Lane for being there when I needed them. I dedicate this thesis to the most precious people in my life, my parents & my wife. 2 Table of Contents Page Acknowledgements..................................................................................................................1 List of Figures...........................................................................................................................4 Chapter 1 Neural Crest Cells and Craniofacial Development...............................................7 Induction of neural crest cells...........................................................................9 Delamination of neural crest cells..................................................................14 Migration of neural crest cells........................................................................16 Pathways specification....................................................................................19 Craniofacial development...............................................................................23 2 Pathogenesis of TCS............................................................................................26 Identification of the TCOF1 gene...................................................................26 Mutations in the TCOF1 gene........................................................................27 Ribosome biogenesis.......................................................................................27 Treacle function..............................................................................................31 Underlying cause of phenotype of TCS..........................................................35 Identification of the apoptosis pathway..........................................................36 3 Animal models of TCS........................................................................................44 Identification of Canine TCOF1.....................................................................44 Identification of Frog TCOF1.........................................................................45 Murine model..................................................................................................46 Zebrafish model..............................................................................................53 4 P53 downstream genes........................................................................................64 3 Introduction.....................................................................................................64 Materials and Methods....................................................................................65 Results.............................................................................................................67 Discussion.......................................................................................................67 Future studies..................................................................................................68 References..............................................................................................................................76 4 List of Figures Page Figure 1: Neural crest cell derivatives.....................................................................................8 Figure 2: Regulation of BMP signaling.................................................................................13 Figure 3: Neural crest cell migration.....................................................................................18 Figure 4: Schematic of pre-rRNA..........................................................................................30 Figure 5: Treacle....................................................................................................................34 Figure 6: Background effect...................................................................................................49 Figure 7: Cleavage period......................................................................................................57 Figure 8: Gastrulation period.................................................................................................58 Figure 9: Blocking translation of ztcof1................................................................................61 Figure 10: Rescue with p53 MO............................................................................................63 Figure 11: In-situ hybridization (p27 probe).........................................................................72 Figure 12: In-situ hybridization (p21 probe).........................................................................73 Figure 13: In-situ hybridization (Bnip3l probe)....................................................................74 5 Abstract IDENTIFICATION OF APOPTOSIS PATHWAY IN TREACHER COLLINS SYNDROME By Khaled Alsayegh, B.S A Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2009 Major Director: Rita Shiang Associate Professor, Department of Human & Molecular Genetics Treacher Collins Syndrome (TCS) is a rare autosomal dominant disorder characterized by severe craniofacial defects. The syndrome is associated with mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein called treacle. Model organisms have been generated to model the disease and have revealed knowledge about the etiology and pathogenesis of the disorder. The craniofacial abnormality observed in TCS patients is found to be caused by an increased level of apoptosis in the neuroepithelium and from this it has been suggested that treacle is important for proper formation and proliferation of neural crest cells that will ultimately contribute to the face. The best attempt to rescue the phenotype of TCS was made by inhibiting the expression of p53 in both zebrafish and mouse models. Although both rescues were successful, it resulted in tumor formation in mice which limits the potential of using this type of rescue in humans. Therefore, it is very important to identify p53-downstream genes that were not 6 related to cancer and use them to interrupt the apoptosis pathway and hence rescuing the phenotype. 7 CHAPTER 1: Neural Crest Cells and Craniofacial Development History of Neural Crest Cells “What role these cells play in the formation of later tissues I do not know, nor do I know what becomes of the “lost” portions of the neural crest which lie between the spinal ganglia, but it has become evident that the whole question of the nature of “mesoderm” in Vertebrates needs revision founded on fact rather than theory.” —J. B. Platt, 1893 Neural crest cells were first called Zwischenstrang, which meant the intermediate cord, when the Swiss embryologist, Wilhelm His, identified these cells sandwiched between the epidermal ectoderm and the neural tube in the neurula stage chick embryos. The neural crest was first named by Arthur Milnes Marshall. (Hall, 1999). In the early
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