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UNIVERSITY of CALIFORNIA Los Angeles UNIVERSITY OF CALIFORNIA Los Angeles Molecular mechanisms underlying sexual differentiation of the brain and behavior A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Human Genetics By Tuck Cheong Ngun 2012 © Copyright by Tuck Cheong Ngun 2012 ABSTRACT OF THE DISSERTATION Molecular mechanisms underlying sexual differentiation of the brain and behavior By Tuck Cheong Ngun Doctor of Philosophy in Human Genetics University of California, Los Angeles, 2012 Professor Eric Vilain, Chair The brains of males and females are different anatomically and chemically. There are also sex differences in neurological disease, cognition and behavior that are presumed to be downstream consequences. Two main factors have been implicated in sexual differentiation of the brain: gonadal hormones and direct genetic effects. Here, we explore the role of sex chromosomes in the brain and behavior and the molecular mechanisms mediating the effects of these factors. We investigated the contribution of sex chromosomes to sex differences in brain and behavior by studying a novel mouse model of Klinefelter Syndrome (KS) termed the Sex Chromosome Trisomy (SCT) model. KS is characterized by the presence of an additional X chromosome in men. We investigated the extent of feminization in XXY male mice. We found that partner preference in XXY males is feminized and that these ii differences are likely due to interactions of the additional X chromosome with the Y. We also found that expression of a small but highly significant proportion of genes is feminized in the bed nucleus of the stria terminalis/preoptic area (BNST/POA) of XXY males, which represent strong candidates for dissecting the molecular pathways responsible for KS- specific phenotypes. We also investigated whether DNA methylation could be one of the molecular mechanisms that mediate the long-lasting, irreversible effects of perinatal testosterone in the BNST/POA. Using a genome-wide approach, we found that methylation at 45 genes was affected three days after the exposure. This number ballooned to 740 in adult animals. There was also a shift to a more masculine pattern of DNA methylation during adulthood in females that had seen perinatal testosterone. These results strongly suggest that perinatal testosterone confers an initial imprint that is amplified over postnatal development. We also observed sex differences in methylation at numerous genes. The interplay between gonadal hormones and sex chromosomes is a complex one. Collectively, our results provide further support for the theory of direct genetic effects in brain sexual differentiation and suggest that DNA methylation may be one mechanism that mediates not only the effects of gonadal hormones but also direct genetic effects. iii The dissertation of Tuck Cheong Ngun is approved. Paul Micevych Aldons J. Lusis Esteban Dell’Angelica Eric Vilain, Committee Chair University of California, Los Angeles 2012 iv DEDICATION For Dayle, who believed in me even when I didn’t believe in myself. You always made sure I was nothing less than fabulous. v TABLE OF CONTENTS Title Page # List of Figures and Tables ix Acknowledgements xi Vita xiii Chapter One: Introduction 1 Overview 2 Sexual Differentiation 3 Sexual Differentiation of the Brain and Behavior A. The Organizational-Activational Hypothesis 5 B. Expansion of the Organizational-Activational hypothesis 8 Sex Differences in Brain and Behavior A. Sex Differences in Neuroanatomy 10 i. The Sexually Dimorphic Nucleus of the Preoptic Area (SDN- 11 POA) ii. The Principal Nucleus of the Bed Nucleus of the Stria 12 Terminalis (BNSTp) B. Sex Differences in Neurochemistry 13 C. Sex Differences in Cognition, Behavior and Neurological Diseases and 15 Disorders Emerging Views vi A. Direct Genetic Effects 17 i. Evidence From the Zebra Finch and Other Avian Species 19 ii. Direct Role of Sry in Brain Sex Differences 20 iii. The ‘Four Core Genotypes’ Model 22 iv. Sex Chromosome Aneuploidies in Humans 24 B. Compensation 26 C. Molecular mechanisms underlying the organizational effect of gonadal hormones i. Cell Death 28 ii. Cellular mechanisms mediating the actions of gonadal 29 hormones iii. Epigenetic mechanisms 30 Conclusion 36 Figures and Tables 38 References 47 Chapter 2: Partner preference and brain gene expression in XXY males from 70 a novel mouse model of Klinefelter Syndrome is feminized Introduction 71 Materials and methods 75 Results 83 Discussion 89 Figures and Tables 97 vii References 108 Chapter 3: The organizational effect of testosterone on the methylome of 117 the BNST/POA is late-emerging and dynamic Introduction 118 Materials and methods 121 Results 125 Discussion 135 Figures and Tables 142 References 151 Chapter 4: Conclusion 158 Genetic influences on sexual differentiation of brain and behavior 160 The molecular mechanisms of sexual differentiation of the brain 163 Conclusion 166 Figures and Tables 169 References 170 viii LIST OF FIGURES AND TABLES Figure 1-1: The catecholaminergic pathway is sexually differentiated Figure 1-2: Serotonin (5-HT) is sexually differentiated on multiple levels Figure 1-3: Sry regulates tyrosine hydroxylase (TH) levels and motor behavior Figure 1-4: The four core genotypes model Table 1-1: Selected neuroanatomical sex differences in the rat Table 1-2: Selected neurochemical sex differences in the brain Figure 2-1: The experimental setup used for this study Figure 2-2: Time spent with the stimulus animal Figure 2-3: Assessment of the degree of feminization of brain gene expression in XXYM Figure 2-4: Quantitative RT-PCR confirmation of feminized genes in XXY males. Figure 2-5: Determination of genes affected uniquely by being XXY Table 2-1: Primers used in the quantitative RT-PCR validation of microarray results Table 2-2: Median time spent with each stimulus animal in seconds Table 2-3: Median number of approaches to the stimulus animals Table 2-4: Top 10 pathways that are significantly affected by being XXY in the BNST/POA (p<0.05 Fisher’s exact test) as determined by Ingenuity Pathway Analysis Table 2-5: Genes that differ in both XXYM vs. XYM and XXM vs. XYM in the BNST/POA Supplementary materials for Chapter 2 are also available ix Figure 3-1: Heat map of normalized 5-mC based on binned data (10-kb bins) identified by hierarchical clustering Figure 3-2: Displayed are the fractions of X, Y, and autosomal genes displaying higher methylation in one sex or the other in the PN60 BNST/POA. Figure 3-3: The number of genes affected by perinatal testosterone exposure. Figure 3-4: Schematic representations of potential scenarios by which testosterone affects CpG methylation in the brain of female mice treated with testosterone Figure 3-5: DNA methylation patterns are more masculine in XX + T at PN60 Figure 3-6: Biological functions affected by both testosterone and non-testosterone do not share many genes Figure 3-7: Global DNA methylation at each age is represented in this figure Table 3-1: Examples of functional categories enriched in the testosterone data-set for the BNST/POA Table 3-2: List of genes where the methylation was stably affected by testosterone Supplementary materials for Chapter 3 are also available Figure 4-1: Model of the late-emerging organizational effect of testosterone on DNA methylation in the BNST/POA x ACKNOWLEDGEMENTS The work presented in Chapters 2 and 3 of this dissertation are based on data from the bed nucleus of the stria terminalis/preoptic area (BNST/POA). However, I would like to take this opportunity to clarify that the work in those chapters are part of a larger project that also included investigation of the striatum by Negar Ghahramani. All data pertaining solely to the striatum have not been included. Firstly, I would first like to acknowledge my mentor, Dr. Eric Vilain, for his guidance, support and tireless energy. Even when things looked their bleakest, he never gave up and was always certain we’d find a way through. I have learned much from Eric, not just about how to be a better scientist but also about how to be a better person. I would also like to offer innumerable thanks to my close friend and collaborator, Negar Ghahramani. This work would have been impossible without her. I could not have wished for a better partner in this endeavor. We did it! Additionally, I would like to thank the esteemed members of my committee – Dr. A. Jake Lusis, Dr. Esteban Dell’Angelica, and Dr. Paul Micevych – for their assistance and direction. None of the projects here would have been possible without the many wonderful collaborators and co-authors listed below with whom I have had the pleasure of working. I have also been truly lucky to have done this work surrounded by an amazing group of scientists in the Vilain lab. Thank you to Dr. Sven Bocklandt, Dr. Alice Fleming, Dr. Saunders Ching, Dr. Francisco Sanchez, Dr. Ruth Baxter, and Dr. Valerie Arboleda. Finally, I’d like to thank the people in my life from whom I drew the strength to see this through: my family and my friends, new and old. Chapter 1 contains excerpts from a review with the following citation: Ngun, T. C.*, Ghahramani, N.*, Sanchez, F. J., Bocklandt, S., Vilain, E. The genetics of sex differences in xi brain and behavior. Front Neuroendocrinol. 2011. 32(2): p. 227-46. Review. * denotes equal contribution. Chapter 2 includes data for future publication. Author list: Tuck C. Ngun*, Negar M. Ghahramani*, Shayna Williams, Michelle N. Creek, Hayk Barseghyan, Yuichiro Itoh, Francisco J. Sánchez, Rebecca McClusky, Janet S. Sinsheimer, Arthur P. Arnold, and Eric Vilain. * denotes equal contribution with regards to the planned publication. Negar Ghahramani helped design and execute the experiments and provided major input on parts of the analysis (detailed in the Introduction to the chapter). Shayna Williams designed, executed and analyzed the motor behavior tests.
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