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

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.

Department dc:contributor.department

Molecular Genetics

Year dc:date.issued

2021

Author dc:creator

• Vashi, Neeti

Advisor dc:contributor.advisor

• Justice, Monica J

• Lipid metabolism
• MECP2
• Pulmonary function
• Pulmonary surfactant
• Rett syndrome
• Translational medicine

Handle dc:identifier.uri

http://hdl.handle.net/1807/105016

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/105016