| Abstract | 第7-8页 |
| 中文摘要 | 第10-12页 |
| List of Abbreviations | 第12-14页 |
| Chapter 1 Introduction | 第14-64页 |
| 1.1. Cardiac development and signaling transduction | 第15-33页 |
| 1.1.1. Cardiac development from cardiac mesoderm | 第15-17页 |
| 1.1.2. Morphogenesis of the cardiac | 第17-20页 |
| 1.1.3. First heart field and second heart field | 第20-22页 |
| 1.1.4. Signaling pathways and transcriptional regulators in cardiac development | 第22-33页 |
| 1.1.4.1 Early signals in cardiac development | 第22-26页 |
| 1.1.4.2. Transcription factors mark cardiac progenitor cells | 第26页 |
| 1.1.4.3. Transcription factors in 1~(st) heart field derivatives | 第26-28页 |
| 1.1.4.4. Transcription factors in 2~(st) heart field derivatives | 第28-33页 |
| 1.2. The role of Hand transcription factors in cardiac morphogenesis | 第33-40页 |
| 1.2.1. Basic Helix-Loop-Helix (bHLH) Transcription Factor | 第33-34页 |
| 1.2.2. Hand Transcription Factors and Cardiovascular Development | 第34-40页 |
| 1.2.2.1. Expression of Hand transcription factors in cardiac development | 第34-35页 |
| 1.2.2.2. Function of Hand transcription factors in cardiac development | 第35-38页 |
| 1.2.2.3. Molecular and cellular mechaniams regulated by Hand2 | 第38-39页 |
| 1.2.2.4. HAND factors in human congenital heart disease (CHD) | 第39-40页 |
| 1.3. Characterization of Pten and its functions in development | 第40-47页 |
| 1.3.1. The discovery of Pten | 第40-41页 |
| 1.3.2. Structure, function and regulation of Pten | 第41-45页 |
| 1.3.2.1. Structure of Pten | 第41-42页 |
| 1.3.2.2 Function of Pten | 第42页 |
| 1.3.2.3. Regulation of Pten | 第42-45页 |
| 1.3.3. Function of Pten in tumorigenesis and embryonic development | 第45-47页 |
| 1.4. Aim and objectives | 第47-49页 |
| 1.5. References | 第49-64页 |
| Chapter 2 The HAND2-FGF-ERK Signaling Controls Proliferation of Second HeartField Progenitor | 第64-94页 |
| 2.1. Introduction | 第65-67页 |
| 2.2. Results | 第67-85页 |
| 2.2.1. Loss of Hand2 resulted in abnormal cardiac morphology | 第67-69页 |
| 2.2.1.1. Generation of Hend2 second heart field-specific knockout mice | 第67页 |
| 2.2.1.2. Ablation of Hand2 resulted in severe cardiac defects | 第67-69页 |
| 2.2.2. Cell proliferation,differentiation,apoptosis and autophagy in Hand2 mutant mice | 第69-71页 |
| 2.2.2.1. Ablation of Hand2 decreased the SHF progenitors and increased myocardial cells apoptosis and autophagy | 第69-71页 |
| 2.2.2.2. Ablation of Hand2 did not affect cell differentiation in the SHF | 第71页 |
| 2.2.3. Molecular studies of Hand2 mutant embryos | 第71-75页 |
| 2.2.3.1. Hand2 mediated activation of FGF-ERK signaling in the SHF development | 第71-73页 |
| 2.2.3.2. The Fgf10 promoter was activated directly by Hand2 | 第73-75页 |
| 2.2.4. Enhancement of phspho-ERK activity by loss of Pten could rescue the defects of cell proliferation in Hand2 mutant embryos | 第75-85页 |
| 2.2.4.1. Ablation of Pten ed to enlarged right ventricle and lengthen outflow tract | 第75-77页 |
| 2.2.4.2. Increased cell proliferation in Pten mulant embryos | 第77-78页 |
| 2.2.4.3. Ablation of Pten ed to premature differentiation of SHF progenitor cells | 第78-80页 |
| 2.2.4.4. Increased both of phspho-ERK and phspho-AKT activity in Pten mutant embryos | 第80-81页 |
| 2.2.4.5. Loss of Pten in the SHF rescued the SHF defects of Hand2 Mutants at molecular level | 第81-83页 |
| 2.2.4.6. Genetic ablation of Hand2 and Pten partially rescued the SHF phenotypes of Hand2 deletion mice | 第83-85页 |
| 2.3. Discussion | 第85-88页 |
| 2.4. Materials and methods | 第88-90页 |
| 2.5. References | 第90-94页 |
| Chapter 3 Pten Function in Second Heart Field is Required for Embryonic andPostnatal Heart Development | 第94-131页 |
| 3.1. Introduction | 第95-96页 |
| 3.2. Results | 第96-118页 |
| 3.2.1. Pten is required for embryonic cardiac development | 第96-98页 |
| 3.2.2. Analysis of cardiac defects in the surviving Pten~(f/f);Mef2c-Cre mice | 第98-105页 |
| 3.2.2.1. Loss of Pten in the second heart field results in cardiac hypertrophy and ventricular septal hyperplasia | 第98-100页 |
| 3.2.2.2. Loss of Pten in the second heart field results in cardiac valve and trabecular defects | 第100-103页 |
| 3.2.2.3. cell morphology abnormal in Pten~(f/f);Mef2c-Cre heart | 第103-105页 |
| 3.2.3. Pten promotes SHF cell proloferation through positvely regulating BMP signaling | 第105-109页 |
| 3.2.3.1. BMP signaling pathway is downregulated in Pten~(f/f);Mef2c-Cre heart | 第105-106页 |
| 3.2.3.2.Bmp7 promoter is directly regulated by Foxo3a in vitro | 第106-109页 |
| 3.2.4. Genetic ablation of Pten and Akt1 rescue RV hypertrophy and extend life span of Pten~(f/f);Mef2c-Cre mice | 第109-110页 |
| 3.2.5. The Combinatorial deletion of Pten and β-catenin partially rescued Pten mutant heart | 第110-112页 |
| 3.2.6. Analysis of Pten~(f/f);mef2c-Cre heart at late stage | 第112-114页 |
| 3.2.7. Chromstin-Remodeling Factors are involved in Pten~(f/f);Mef2c-Cre mice | 第114-118页 |
| 3.3. Discussion | 第118-121页 |
| 3.4. Materials and methods | 第121-126页 |
| 3.4.1. Animal studies | 第121-124页 |
| 3.4.2. Molecular studies | 第124-126页 |
| 3.5. References | 第126-131页 |
| Curriculum Vitae:Wen Luo | 第131-133页 |
| 致谢 | 第133-134页 |
