{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/105016"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/105016","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome","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 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.","abstract_html":"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 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.","abstract_has_math":false,"creators":["Vashi, Neeti"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Molecular Genetics","school":null,"contributors":[],"advisors":["Justice, Monica J"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-03","date_published":"2021-03","updated_at":"2026-07-27T21:28:05Z","subjects":["Lipid metabolism","MECP2","Pulmonary function","Pulmonary surfactant","Rett syndrome","Translational medicine"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/105016","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Justice, Monica J"]},{"key":"dc:contributor.department","label":"Department","values":["Molecular Genetics"]},{"key":"dc:creator","label":"Author","values":["Vashi, Neeti"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2021-03"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2021-03-15T14:53:39Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2021-03-15T14:53:39Z"]},{"key":"dc:date.issued","label":"Date","values":["2021-03"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Lipid metabolism","MECP2","Pulmonary function","Pulmonary surfactant","Rett syndrome","Translational medicine"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/105016"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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 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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome"]}]}],"canonical_facts":{"dc:contributor.advisor":["Justice, Monica J"],"dc:contributor.department":["Molecular Genetics"],"dc:creator":["Vashi, Neeti"],"dc:date":["2021-03"],"dc:date.accessioned":["2021-03-15T14:53:39Z"],"dc:date.available":["2021-03-15T14:53:39Z"],"dc:date.issued":["2021-03"],"dc:description.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 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."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1807/105016"],"dc:subject":["Lipid metabolism","MECP2","Pulmonary function","Pulmonary surfactant","Rett syndrome","Translational medicine"],"dc:title":["Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:05Z"}