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Eph and Ephrins in Palate Development

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Eph and Ephrins in Palate Development EPH AND EPHRINS IN PALATE DEVELOPMENT A Dissertation by MARIA JULIANA SERRANO Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Kathy Svoboda Co-Chair of Committee, Lynne Opperman Committee Members, Bruno Ruest Emet Schneiderman Reginald Taylor Head of Department, Paul Dechow May 2015 Major Subject: Biomedical Sciences Copyright 2015 Maria Juliana Serrano ABSTRACT Cleft palate (CP) is one of the most common birth defects. It may not be life threatening but many functions, such as feeding, digestion, speech, middle-ear ventilation, hearing, respiration, and facial and dental development, can be disturbed because of the structures involved. These problems can also cause emotional, psychosocial, and educational difficulties. It imposes a tremendous health burden and often leaves lasting disfigurement. In humans and mice, the secondary palate forms from outgrowths of neural crest-derived mesenchyme covered with a double layer of epithelial cells. The shelves elevate over the tongue and grow toward each other. The medial edge epithelium (MEE) adheres to form the medial epithelial seam (MES). MES cells then undergo epithelial to mesenchymal transition (EMT), cell apoptosis or migrate to the oral and nasal surfaces to form a mesenchymal cell confluence. This fusion process requires transforming growth factor β3 (TGFβ3), and blocking the expression of this protein or its downstream signaling cascade results in CP. Eph receptors tyrosine kinases and their ephrin ligands are responsible for multiple developmental events such as adhesion and migration. Binding of ephrins to Ephs on opposing cells causes tyrosine kinase activation in the Eph- bearing cells (forward signaling), while binding of Ephs can activate intracellular signaling inside ephrin- bearing cells (reverse signaling). Activation of ephrin reverse signaling in chicken palates induces fusion, and it requires phosphatidylinositol-3 kinase (PI3K). Blockage of reverse signaling inhibited TGFβ3 induced fusion in the chicken and natural fusion in ii the mouse palate. Thus, ephrin reverse signaling is necessary to induce palate fusion independent of TGFβ3. EMT is orchestrated by a complex network of signaling molecules and it is a critical step for palatal fusion. TGFβ family is a multifunctional cytokine that oversees and directs all aspects of cell development, differentiation and survival of essentiall cell types and tissues. Also, it is a suppressor of cell growth and proliferation particularly in tumor cells of epithelial and mesenchymal origins. Ephrin signaling promotes elevation of TGFβ signaling. These findings lead to the central hypothesis that the TGFβ and Eph/ephrin pathways cooperate in EMT in palatal fusion. Thus, the goal of this research project is to use the palate model system to generate cellular responses and changes to study the basic mechanisms that control EMT during palatogenesis. Therefore the aims of this work are as follows: a) Determine if Eph and ephrins play a role in palatal fusion and b) Establish if ephrin reverse signaling is necessary and sufficient to induce EMT in palatal fusion independent of TGFβ. iii DEDICATION To God for providing me with the inspiration, perseverance and strength to pursue my dreams. To my mother, husband, son, family and friends for their love, understanding and support during this long journey. iv ACKNOWLEDGEMENTS I would like to thank my committee chair: Dr. Kathy Svoboda. This dissertation could not have been written without her mentoring and direction. During my Ph.D. program, Dr. Svoboda not only served as my advisor, but she also set high standards in our lab by being an outstanding scientist in this field. I am proud to be one of her students, and I will try to emulate her spirit and persistent drive towards the advancement of science for the rest of my life. My deepest gratitude also to my committee members, Dr. Lynne Opperman, Dr. Emet Schneiderman, Dr. Bruno Ruest and Dr. Reginald Taylor for their guidance and support throughout the course of this research. I sincerely thank my husband Alexander Reyes and my son Sebastian Reyes for all their patience, support and most importantly their unconditional love. Also, thanks to my wonderful friends Liliana Mantilla, Claudia Mantilla, Cynthia Cobb, Claudia Fernandez, Ashneet Sachar, Symone San Miguel, Monica Prasad, Poova Gharpore, Leslie Pryor, Fatma Mohammed, Priyam Jani, Aditi Bhattacharya, Rene Yin Shi, and Isra Mohammed for their friendship and support. v NOMENCLATURE A-P Anterior to Posterior ADAMTS Disintegrin And Metalloproteinase with Thrombospondin Motifs ANOVA The Analysis Of Variance ASCs Adipose Stem Cells ATCC Cell lines BMP Bone morphogenetic proteins Cbf Core Binding proteins CD1 Cluster of differentiation (cell surface protein) CHO-K1 Cell line CL Cleft Lip CLP Cleft Lip and Palate CNC Neural Crest Derived CP Cleft Palate DNA Deoxyribonucleic acid DO Distraction Osteogenesis ECM Extracellular Matrix EGFR Epidermal Growth Factor Receptor EMT Epithelial Mesenchymal Transition Eph Erythropoietin-producing human hepatocellular carcinoma cell ERK Extracellular signal-regulated kinases vi Fc Crystalized fraction Fgf Fibroblast Growth Factor FgfR Fibroblast Growth Factor Receptor FOXE1 Forkhead Box Protein E1 GABA Gamma Aminobutyric acid GPI Glycosylphosphatidyl-inositol GRIP1 Glutamate receptor interacting protein GSK Glycogen synthase kinase GSTT Glutathione S-transferase theta H&E Hematoxylin and Eosin HA Hydroxyapatite hh Hedge hog Ig G Immunoglobulin G Irf Interferon Regulatory Factor Lhx LIM homeobox MAPK Mitogen-activated protein kinases MEE Middle Edge Epithelium MES Medial epithelial Seam MFS Mean Fusion Score Mmps Matrix metaloproteinases MP Mid Palatal mRNA Messenger RNA vii MSCs Mesenchymal Stem Cells Msx1 Msh homeobox 1 NFAT Nuclear Factor of Activated T-cells NS Nonsyndromic NOS Nitric oxide synthase OO Orbicularis Oris OR Odds Ratio Osr Protein odd-skipped-related Pax Paired box PDGF Platelet-derived growth factor PI3K Phosphatidylinositol-3 Kinase PLA Poly lactic acid PLGA Poly lactic glycolic acid RTKs Receptor Tyrosine Kinases SEM Standard error of the Mean SH2 Src Homology 2 (Binding Domain) Shh Sonic hedge hog Shox2 The short stature homeobox siRNA Small interfering RNA SPSS Statistical Package for the Social Sciences SUMO Small ubiquitin-like modifier SVF Stromo-Vascular Fraction viii Tbx22 T-box transcription factor TGFβ3 Transforming Growth Factor β3 Tim Tissue inhibitor of metalloprotein TP Trans Palatal VAX1 Ventral anterior homeobox 1 ix TABLE OF CONTENTS Page ABSTRACT ................................................................................................................. ii DEDICATION ............................................................................................................. iv ACKNOWLEDGEMENTS ......................................................................................... v NOMENCLATURE ................................................................................................... vi TABLE OF CONTENTS ............................................................................................ x LIST OF FIGURES ..................................................................................................... xiii LIST OF TABLES ....................................................................................................... xiv CHAPTER I INTRODUCTION AND LITERATURE REVIEW ............................ 1 Palate Development .............................................................................................. 2 Molecular Genetics Behind Cleft Palate ............................................................. 3 TGFβ3 ........................................................................................................... 4 Ephs and Ephrins .......................................................................................... 5 PDGF Signaling ............................................................................................ 6 Wingless Type (Wnt) Protein Signaling ....................................................... 6 Irf 6 (Interferon Regulatory Factor 6) ........................................................... 7 VAX1 ........................................................................................................... 7 ADAMTS Family Metalloproteases ............................................................. 8 Fibroblast Growth Factor 10 (Fgf10) ........................................................... 8 FOXE1 (Forkhead Box Protein E1) .............................................................. 9 Molecular Signaling Events in Embryonic Palatal Development ........................ 9 Failure of Palatal Shelf Formation ................................................................ 9 Fusion of the Palatal Shelf with the Tongue or Mandible ............................ 11 Failure of Palatal Elevation ........................................................................... 12 Failure of Palatal Shelves to Meet After Elevation ...................................... 13 Persistence of Middle Edge Epithelium ........................................................ 13 SUMO Modification of Signaling Pathways in Palatogenesis ............................. 14 A-P Gradient of Molecular Signaling in Palatal Development ............................ 16 Types of Cleft Palate ..........................................................................................
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