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II Preface  IV Table of contents  V List of tables IX List of figures  X List of abbreviations  XI Acknowledgements  XIV Dedication  XV Chapter 1: Introduction: 1 1.1 Overview of the research plan  1 1.2 Prevalence of orofacial clefts  6 1.3 The origin of cells in the palate 8 1.4 The process of palatogenesis  9 1.4.1 Human palatal development  9 1.4.2 Mouse palatal development  13 1.4.3 Disparities between mouse and human anatomical development 16 1.5 Syndromic cleft lip, with or without cleft palate  17 1.6 Non-syndromic cleft lip, with or without cleft palate  19 1.6.1 Epidemiology of non-syndromic cleft lip, with or without cleft palate  19 1.6.2 Genetic etiology  20 1.6.3 Environmental risk factors  20 VI 1.6.4 NSCL/P and genetic studies 22 1.7 TGF-β signaling  23 1.7.1 SMAD-dependent TGF-β signaling pathway  24 1.7.2 SMAD-independent TGF-β signaling pathway  24 1.8 Mouse craniofacial phenotypes and deletion of TGF-β signaling genes  25 1.8.1 TGF-β1 null (TGF-β1) mice  25 1.8.2 TGF-β2 null (TGF-β2) mice  25 1.8.3 TGF-β3 null (TGF-β3) mice  26 1.8.4 TβRI, TβRII and TβRII null mice.  26 1.8.5 SMAD2 null mice  27 1.8.6 SMAD3 and SMAD4 null mice  27 1.9 Experimental mammalian models: mice in the study of cleft lip and palate  28 1.9.1 Experimental mammalian models: K14-SMAD2 mouse phenotype 29 1.9.2 TGF-β3 and K14-SMAD2/TGF-β3 mice phenotype  29 Chapter 2: Medial edge epithelium 31 2.1 Fate of medial edge epithelium  31 2.1.1 Apoptosis (programed cell death)  32 2.1.2 Epithelial-mesenchymal transdifferentiation  33 2.1.3 Cell migration  36 2.2 The role of twist1 and collagen IV during palatal development  37 2.3 How cells die: apoptosis, autophagy and necrosis  41 2.3.1 Cell death  41 2.3.2 Differences between mechanism of cell death.  42 VII 2.4 TGF-β and apoptosis.  43 2.5 Mechanism of apoptosis  45 2.6 Apoptosis detection methods  47 2.6.1 TUNEL technique  47 2.6.2 Immunohistochemistry detection of apoptosis related caspase-3  48 2.7 Hypothesis 49 2.8 Aims and objectives  49 Chapter 3: Materials and methods 50 3.1 Animal breeding 50 3.2 Animal genotyping 50 3.3 Histology and immunohistochemistry  52 3.3.1 Fixation and paraffin embedding of the samples  52 3.3.2 Hematoxylin and eosin  53 3.3.3 Deparaffinization of tissue sections and rehydration  54 3.3.4 Antigen retrieval and background stain blocking  54 3.3.5 Analysis of MEE apoptosis rate TUNEL technique  55 3.3.6 Analysis of MEE apoptosis rate ccaspase3 technique  56 3.3.7 Analysis of MEE phosphorylated-SMAD2 rate  57 3.3.8 Analysis of MEE twist1 and collagen IV expression  58 3.4 Confocal laser microscopy  59 3.5 Statistical analysis  60 Chapter 4: Results and conclusion 61 4.1 Increased MEE cell apoptotic rate.  61 VIII 4.2 Increased levels of activated “phosphorylated” SMAD2 in the MEE  67 4.3 Loss of basement membrane in the MEE cell and twist1 positive cells.  69 4.4 Discussion  72 4.4.1 SMAD2 overexpression rescues palatal fusion by inducing apoptosis  73 4.4.2 Evidence of EMT mechanism and basement membrane degradation.  74 4.5 Conclusion  75 Bibliography 76

Smad2 overexpression rescues the tgf- 3 null mutant mice cleft palate by increased apoptosis