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Ventral Hindgut and Bladder Development

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Ventral Hindgut and Bladder Development Ventral Hindgut and Bladder Development by Wei CHENG A thesis submitted in conformity with the requirements For the degree of PhD Graduate Department of Institute of Medical Science University of Toronto © Copyright by Wei Cheng, 2008 Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-40009-8 Our file Notre reference ISBN: 978-0-494-40009-8 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada Thesis Abstract VENTRAL HINDGUT AND BLADDER DEVELOPMENT Wei CHENG Doctor of Philosophy Institute of Medical Science University of Toronto 2008 Developmental anomalies of the bladder pose a great challenge to pediatric urologists. Yet the mechanisms regulating the developmental biology of the bladder remain poorly understood. Bladder development involves epithelial-mesenchymal interaction. p63 is expressed in all stratified epithelia including the bladder urothelium. We have established that the N-terminal truncated isoform of p63, ANp63, is preferentially expressed in the ventral bladder urothelium during early organogenesis. p63~A embryos developed ventral midline defects affecting the ventral bladder and abdominal walls, reminiscent of bladder exstrophy, a congenital anomaly exhibited in human neonates. The p63 deficient ventral urothelium was neither stratified nor differentiated. It had significantly increased apoptotic activity and reduced cell proliferation. This is accompanied by failure to induce mesenchyme. Over-expression of ANp63 in p63'A bladder primary cell cultures rescued the apoptosis. We conclude that ANp63 plays a crucial anti-apoptotic role during bladder development. The absence of ANp63 leads to ventral urothelial apoptosis, failure of mesenchymal development and bladder exstrophy. ii Shh is a candidate epithelial signal in the bladder epithelial mesenchymal interaction. The mechanism by which Shh regulates bladder development remains unclear. In the wild-type developing bladders, Shh was expressed in the epithelium whereas its transcriptional factor GH2 and its target gene Bmp4 were expressed in the inner mesenchymal zone, which also contained more proliferating cells. In the outer mesenchymal zone, where GH2 and Bmp4 expressions were not detectable, smooth muscle a-actin expression was detected. In GH2~/~ embryo bladders, normal Bmp4 expression in the inner zone was lost. The normal radial pattern of inner zone of cell proliferation and outer zone of smooth muscle differentiation was replaced by disorganized cell proliferation and ectopic smooth muscle in the inner zone. Using primary murine bladder mesenchymal cell cultures, we demonstrated that transfection with ANGH2 adenoviruses up-regulated Bmp4 expression and addition of Bmp4 protein (lOmg/ml) repressed smooth muscle differentiation. We conclude that Shh transcriptional factor GH2 regulates the bladder mesenchymal patterning. iii Acknowledgements This work would not have been possible without the opportunity to conduct basic science research afforded me by my supervisors, Dr. Peter C.W. Kim and Dr. Chi-Chung Hui. I thank them for their patience and guidance. Although I carried out most of the experimental work presented here, I benefited greatly from the technical assistance and friendship of my colleagues in Dr. Kim's laboratory, namely, Dr. Jennifer Jian-Rong Zhang, Dr. Guo-Dong Liu, Ms. Michelle Kushida, Dr. Anne Moro, Ms. Jin-hyung Park. My colleagues in Dr. Hui's laboratory also deserve mention for their advice and technical instruction; Dr. Pleasantine Mill, Dr. Erica Nuiwenhuis, and Dr. Rong Mo. In addition, I am most grateful to Dr. Wei Qiu of the Research Institute, Hospital for Sick Children, for his technical support to the key experiment. I very much enjoyed my collaboration with Dr. W. Bradley Jacobs, Dr. Freda Miller and Dr. Alea Mills on the study of p63v~ mutant mice, and am grateful to both Professor Jacob Langer, Department of Surgery, and Dr. Neil Sweezey, Clinician Scientist Program Coordinator, Hospital for Sick Children, for their advice and encouragement. Invaluable financial support was received from the Division of General Surgery, Department of Surgery, Research Trainee Competition Fund of the Institute of Research, and a Clinician Scientist Scholarship from the Hospital for Sick Children, Toronto. Finally, my loving wife, Karin Moorhouse deserves special mention. I thank her for unwavering support throughout my studies, for sharing the ups and downs, and above all for making her own career sacrifices which enabled me to realize my dream. IV Table of Contents Chapter 1 Introduction 1 A clinical problem 2 Bladder Structure and embryology 2 Bladder structure 3 Endoderm, gut, and bladder embryology 4 Gut, Hindgut and Bladder Developmental biology 6 Endodermal genes 6 Hindgut genes 7 Mesenchymal-epithelial interaction in gut and bladder 8 Epithelial signal in bladder development 9 p63 regulates the development of stratified epithelium 10 Sonic hedgehog (Shh) as a urothelial signal 17 Mesenchymal development 22 Bone morphogenetic protein-4 (Bmp4) in mesenchyme development 22 Bladder mesenchymal cells differentiate into smooth muscle cells 25 Working Model 27 Chapter 2 Hypothesis 28 Hypothesis 1 29 Questions 29 Hypothesis 1 29 Test of the hypothesis 29 Hypothesis 2 31 Questions 31 Hypothesis 2 32 Test of the hypothesis 32 Chapter 3 ANp63 plays an anti-apoptotic role in ventral bladder development33 Abstract 34 Introduction 35 v Materials and Methods 37 p63~/~ mutant mice genotyping 37 Histochemistry and immunohistochemistry 38 RNA extraction, qPCR, and RT-PCR 39 Immunoblot 40 Organ culture, primary cell culture, and transfection 41 In-situ hybridization 42 Results 43 P63 deficiency leads to bladder exstrophy 43 p63 is expressed in bladder epithelium throughout its development and the ANp63 is the predominant isoform 45 p63 expression is ventrally restricted during early bladder development 47 p63-deficient bladder epithelium is abnormal along the dorso-ventral axis 48 Apoptosis is increased in p63-deficient bladder epithelium 52 ANp63 is anti-apoptotic during bladder development 55 Apoptosis of bladder cells of El 2.5 p63~/' mutants is associated with an upregulation of p53 and p73 expressions 57 Failure of ventral UGS mesenchymal induction and proliferation in the absence of epithelial ANp63 57 Smooth muscle differentiation is disturbed in p63-deficient bladders 61 Discussion 63 Early ventral p63 expression and ventral midline defects in p63"A mutants 63 Temporospatial restriction of p63 expression determines epithelial commitment to stratification and differentiation 65 ANp63 is prosurvival in ventral bladder development 66 Chapter 4 Shh transcriptional factor GU2 regulates bladder mesenchymal patterning69 Abstract 70 Introduction 71 Methods 74 Mutation Analysis 74 Primary cell cultures and transfection 74 VI Immunoblot 75 Immunohistochemistry and TUNEL 76 RNA extraction and the real time PCR 76 In-situ hybridization 77 Results 77 Shh signaling is active in bladder development 77 GH2 promotes cell proliferation in the inner mesenchymal zone 79 GH2 represses smooth muscle differentiation in the bladder 82 GU2 up-regulates Bmp4 expression in the sub-epithelial bladder mesenchyme 84 Bmp4 Represses Bladder Smooth Muscle Differentiation 85 Epithelial mesenchymal interaction 87 Discussion 88 Shh transcriptional factor GH2 regulates the radial patterning of the bladder mesenchyme 89 GU2 regulates the smooth muscle differentiation via its action on Bmp4 91 Working Model 93 Chapter 5 Conclusions and future directions 95 Conclusions 96 p63 is anti-apoptotic in ventral bladder development 96 Shh transcriptional factor GH2 regulates the patterning of a developing bladder 96 Future Directions 97 Is early p63 expression a marker for epithelial organizer during morphogenesis? 97 p63 screening in
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