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In Vivo Analysis of Human Lhx3 Enhancer Regulation

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In Vivo Analysis of Human Lhx3 Enhancer Regulation IN VIVO ANALYSIS OF HUMAN LHX3 ENHANCER REGULATION Soyoung Park Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology, Indiana University March 2013 Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Simon J. Rhodes Ph.D., Chair Richard N. Day Ph.D. Doctoral Committee Maureen A. Harrington Ph.D. January 29, 2013 B. Paul Herring Ph.D David G. Skalnik Ph.D ii © 2013 Soyoung Park ALL RIGHTS RESERVED iii DEDICATION I dedicate this dissertation to my family and my husband Cheolwoong. Without their love and support I would never have reached this point. iv ACKNOWLEDGMENTS I would like to acknowledge the members of my graduate committee: Dr. Simon Rhodes, Dr. Paul Herring, Dr. Richard Day, Dr. David Skalnik, and Dr. Maureen Harrington. Your insight and helpful support has been invaluable. I would like to thank past and present Rhodes’ lab members: Dr. Rachel Mullen, Dr. Stephanie Colvin, Raleigh Malik, Dr. Kelly Prince, Rachael Basden, and Josh Horton. I would also like to thank the Department of Biochemistry and Molecular Biology faculty and staff, I especially wish to acknowledge Dr. Hyun-Suk Lim, Dr. Misuk Oh, and Dr. Mark Goebl. During my graduate career I have been fortunate to be a visiting member of the Department of Cellular and Integrative Physiology and wish to thank the faculty, students and staff for making me feel like a part of their department. Lastly, I would like to express my sincere gratitude to my advisor and mentor, Dr. Simon J. Rhodes, for his guidance and encouragement throughout my graduate studies. It was my honor to be part of his lab. Thank you for your patients and wise advice both in science and life. I will not forget your mentorship and friendship. Thank you Simon. v ABSTRACT Soyoung Park IN VIVO ANALYSIS OF HUMAN LHX3 ENHANCER REGULATION The LHX3 transcription factor is essential for pituitary gland and nervous system development in mammals. In humans, mutations in the LHX3 gene underlie combined pituitary hormone deficiency (CPHD) disease featuring deficits in anterior pituitary hormones and defects in the nervous system. The mechanisms that control temporal and spatial expression of the LHX3 gene are poorly understood. The proximal promoters of the human LHX3 gene are insufficient to guide expression in vivo and downstream elements including a conserved 7.9 kilobase (kb) enhancer region appear to play a role in tissue-specific expression in the pituitary and nervous system. In this study, I characterized the activity of this downstream enhancer region in regulating gene expression at the cellular level during development. Human LHX3 enhancer-driven Cre reporter transgenic mice were generated to facilitate studies of enhancer actions. The downstream LHX3 enhancer primarily guides gene transcription in αGSU-expressing cells secreting the TSHβ, LHβ or FSHβ hormones and expressing the GATA2 and SF1 transcription factors. In the developing nervous system, the enhancer serves as a targeting module for expression specifically in V2a interneurons. These results demonstrate that the downstream LHX3 enhancer is important in specific endocrine and neural cell types but also indicate that additional regulatory elements are likely involved in LHX3 gene vi expression in other cell types. Further, these studies demonstrate significant gonadotrope cell heterogeneity during pituitary development, providing insights into the cellular physiology of this key reproductive regulatory cell. The human LHX3 enhancer-driven Cre reporter transgenic mice provide a valuable tool for further developmental studies of cell determination and differentiation in the pituitary and nervous system. Furthermore understanding the regulation of human LHX3 gene will help develop tools to better diagnose and treat pituitary CPHD disease. Simon J. Rhodes Ph.D., Chair vii TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES .............................................................................................................x LIST OF ABBREVIATIONS ........................................................................................... xii CHAPTER ONE – INTRODUCTION 1.1 The Pituitary Gland and its Hormones.....................................................................1 1.2 Pituitary Development .............................................................................................3 1.3 Signaling Molecules in Early Pituitary Development ............................................ 4 1.4 Transcription Factors in Anterior Pituitary Development .......................................6 1.5 LIM-HD Transcription Factors, ISL1, LHX4, and LHX3.....................................12 1.6 Central Hypothesis and Aims ................................................................................19 CHAPTER TWO – MATERIALS AND METHODS 2.1 DNA Cloning and Vector Construction .................................................................31 2.2 Generation, Genotyping and Breeding of Transgenic Mice ..................................32 2.3 Histology and Immunohistochemistry ...................................................................34 2.4 Microscopy ............................................................................................................37 2.5 General Molecular Techniques ..............................................................................38 2.6 Quantitation and Statistical Analyses ....................................................................40 CHAPTER THREE – IN VIVO ANALYSIS OF HUMAN LHX3 ENHANCER REGULATION 3.1 Results ....................................................................................................................42 CHAPTER FOUR – DISCUSSION AND CONCLUSIONS ...........................................68 REFERENCES ..................................................................................................................80 CURRICULUM VITAE viii LIST OF TABLES Table 1.1 Mutations within the LHX3 gene associated with combined pituitary hormone deficiency disease .......................................................................................................30 3.1 Genotypes of progeny from ELHX3CRE/+ and R26DTA/+ crosses .................................67 ix LIST OF FIGURES Figure 1.1 Regulation of the development of anterior pituitary gland hormone- expressing cells by signaling molecules and transcription factors ...........................22 1.2 The human LHX3 gene spans approximately 8.7 kb of sequence and contains seven exons and six introns ........................................................................23 1.3 DAN analysis reveals a novel novel homozygous mutation (T194R) in the LHX3 gene in patients with CPHD ...........................................................................24 1.4 Structural prediction of LHX3 homeodomain/DNA interaction ..............................25 1.5 The LHX3 T194R protein does not bind to LHX3 DNA recognition elements and is not able to activate a pituitary target gene.......................................26 1.6 Two basal promoters of the human LHX3 gene are not sufficient to drive transgene (LacZ) activity in vivo ..............................................................................27 1.7 A conserved distal downstream regions (~7.9 kb) of the human LHX3 gene can direct expression to the developing pituitary and spinal cord in vivo ................28 1.8 7.9 kb 3′ enhancer-directed transgene expression coincides with native LHX3 expression ......................................................................................................29 2.1 3´ LHX3 enhancer region-HSP68 promoter modified pBS594-EGFP-Cre transgene ...................................................................................................................41 3.1 The endogenous mouse LHX3 protein and a human LHX3 gene 3′ enhancer- guided reporter gene are expressed in anterior pituitary αGSU-expressing thyrotropes and gonadotrope cells, but not in somatotropes and corticotropes ........53 3.2 The 3′ enhancer from the human LHX3 gene directs Cre recombinase expression in the developing and neonatal anterior pituitary gland and spinal cord ...........................................................................................................................55 3.3 The human 3′ LHX3 enhancer is active in many αGSU-expressing anterior pituitary cells .............................................................................................................56 x 3.4 Thyrotropes and gonadotropes lineages are reduced in neonatal ELHX3CRE/+/R26DTA/+ mice .......................................................................................58 3.5 LHβ-expressing cells are strikingly ablated in ELHX3CRE/+/R26DTA/+ mice and LHβ cells co-localize with FSHβ and SF1 .........................................................60 3.6 LHX3-expressing IN cells are reduced in the V2 IN region of the developing spinal cord in ELHX3CRE/+/R26DTA/+ mice but MN populations are unaffected ............................................................................................................62 3.7 LHX3- and CHX10-expressing V2a interneuron cells are reduced in the spinal cord of ELHX3CRE/+/R26DTA/+ mice ................................................................64
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