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Lung Defects Contribute to Respiratory Symptoms in a Mecp2-Mutant Mouse Model of Rett Syndrome

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Lung Defects Contribute to Respiratory Symptoms in a Mecp2-Mutant Mouse Model of Rett Syndrome Lung Defects Contribute to Respiratory Symptoms in a Mecp2-Mutant Mouse Model of Rett Syndrome by Neeti Vashi A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Molecular Genetics University of Toronto © Copyright by Neeti Vashi 2021 Lung Defects Contribute to Respiratory Symptoms in a Mecp2- Mutant Mouse Model of Rett Syndrome Neeti Vashi Doctor of Philosophy Molecular Genetics University of Toronto 2021 Abstract Rett syndrome (RTT) is a progressive neuro-metabolic disorder caused by mutations in the X- linked gene, methyl-CpG-binding protein 2 (MECP2). After a period of seemingly normal post- natal development, RTT patients experience a developmental regression, consisting of loss of acquired verbal and motor skills, stereotypic hand movements, respiratory abnormalities, and seizures. Respiratory impairment causes up to 80% of premature patient death; despite this, lung pathology in RTT is understudied and respiratory symptoms are currently attributed to neuronal loss of MECP2. To study the Mecp2-deficient lung, we utilized a Mecp2-mutant mouse model that recapitulates many features of RTT. I found striking lipid metabolism abnormalities in the lungs of Mecp2-mutant mice, including increased cholesterol and triglycerides and decreased phosphatidylcholines. My single cell RNA-sequencing and chromatin immunoprecipitation experiments showed that lipogenesis is increased due to decreased binding of the nuclear repressor coreceptor 1/2 (NCOR1/2) complex in the promoters of its target genes in the absence of MECP2, leading to their upregulation. I also showed that lung AE2 cell-specific depletion of Mecp2 is sufficient to cause lung lipid metabolism abnormalities and respiratory symptoms. In contrast, hindbrain neuron-specific deletion of Mecp2, which removes Mecp2 from the neuronal respiratory control center, imparted a different respiratory phenotype. RNA-sequencing of the Mecp2-deficient lung revealed decreased expression of key extracellular matrix (ECM) genes; consistently, I found alveolar tissue degradation and bronchiolar enlargement in Mecp2-mutant ii mice. Consistent with these findings, Mecp2-mutant mice have altered pulmonary function. Finally, we treated whole body metabolism in Mecp2-mutant mice using lipid-modulating compounds, including statins and liver X receptor (LXR) agonists; both improved neurological and respiratory symptoms, suggesting clinical utility. Altogether, these findings implicate key functions of Mecp2 in the lung and highlight the importance of studying non-neuronal aspects of RTT. Our findings will aid in developing treatments and clinical recommendations for RTT patients. iii Acknowledgments I would first like to express my sincere gratitude to my advisor, Dr. Monica Justice. Your contagious enthusiasm, accurate instincts, and thirst for scientific knowledge continue to amaze me. You have always pushed me outside of my comfort zone, and I have grown tremendously as a scientist, and as a person, because of it. it. Thank you for providing me with numerous opportunities that I will always cherish. I am lucky to have been mentored by you and I will always be grateful that you saw my potential. To my supervisory committee, Dr. Lucy Osborne and Dr. Martin Post: I genuinely enjoyed my committee meetings because of your thoughtful guidance, support, and discussions. Thank you to our collaborators, Dr. Cameron Ackerley, Dr. Pradip Saha, Dr. Gillian Sleep, and individuals at the Center for Phenogenomics, The Center for Applied Genomics, the Analytical Facility for Bioactive Molecules, and the Princess Margaret Genomics Centre, without whom this work would not have been possible. I have been extremely fortunate to have worked alongside many talented individuals in an incredibly supportive environment. SMK, thank you for your patient mentorship during my first two years of graduate school. To the current members of the Justice lab, correction, family (AE, CT, JR, LH, LT, RT, ZK): thank you for the stimulating scientific discussions and equally stimulating distractions. Each of you has contributed so much to my journey, both scientific and personal, and I am forever grateful. Thank you to the drug study team, JR and CT; I’ll cherish all the hours we spent in fume hoods together. ZK, thank you for always being so willing to help me out, especially during the pandemic. JR, you have been essential to my success – this PhD would have taken an extra three years without you! I would not have been able to accomplish this without the encouragement of my family. To my parents, I will always be immensely grateful for the sacrifices you made in order for me to have the best educational opportunities. Thank you for being my biggest supporters – I hope I always make you proud. To my brother, PV, thank you for being someone I will always look up to, and to my sister-in-law, RV, for always providing a positive outlook. I am extremely grateful to my friends for endless encouragement and for getting excited about science. Finally, to my incredible partner, KJ, who has listened to me practice my presentations so many times, he probably has my project memorized. Thank you for always encouraging me on the bad days and celebrating all the good ones; this would not have been possible without you. iv Table of Contents Acknowledgments ...................................................................................................................... iv Chapter 1 Introduction and Background .................................................................................... 1 Introduction and Background ................................................................................................. 2 1.1 A brief description of Rett syndrome ............................................................................... 2 1.1.1 Rett syndrome diagnosis and stages ................................................................... 2 1.1.2 Stage-independent features of Rett syndrome .................................................... 6 1.1.3 Classic RTT is caused by mutations in MECP2 ................................................... 8 1.1.4 Atypical Rett syndrome ....................................................................................... 8 1.1.5 The MECP2 gene ................................................................................................ 8 1.1.6 The MECP2 protein and its isoforms ................................................................. 10 1.1.7 MECP2 domains ............................................................................................... 12 1.1.8 RTT-causing MECP2 mutations ........................................................................ 15 1.1.9 Phenotypic variation in RTT .............................................................................. 17 1.1.10 MECP2 expression and localization .................................................................. 19 1.1.11 MECP2 function ................................................................................................ 19 1.1.12 Males with MECP2 mutations ............................................................................ 25 1.2 Studying MECP2 using animal models ......................................................................... 27 1.2.1 Mecp2-null mouse models................................................................................. 27 1.2.2 Male vs. female Mecp2-mutant mice ................................................................. 31 1.2.3 Similarities between Mecp2-mutant mice and RTT patients .............................. 31 1.2.4 Mecp2-mutant mice with human RTT-causing mutations .................................. 33 1.2.5 Temporal deletions of Mecp2 ............................................................................ 33 1.2.6 Symptom reversal and suppression in Mecp2-mutant mice ............................... 34 1.3 Regulation of breathing ................................................................................................. 44 1.3.1 Autonomic control of respiratory rhythm ............................................................ 46 1.3.2 Lung development ............................................................................................. 49 1.3.3 Cellular composition of the lung......................................................................... 51 1.3.4 Pulmonary surfactant ........................................................................................ 54 1.3.5 The lung’s extracellular matrix ........................................................................... 57 1.3.6 Respiratory disorders ........................................................................................ 57 1.3.7 Breathing abnormalities in RTT ......................................................................... 61 1.4 Hypothesis .................................................................................................................... 63 Chapter 2 Lung lipid defects contribute to respiratory symptoms in a Mecp2-mutant mouse model of Rett syndrome ....................................................................................................... 64 v Lung lipid defects contribute to respiratory symptoms in a Mecp2-mutant mouse model of Rett syndrome ..................................................................................................................... 65 2.1 Abstract .......................................................................................................................
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