UC San Diego
Role of Microglia in Rett Syndrome Pathogenesis using induced-Pluripotent Stem Cells
- Author(s): Jeziorski, Jacob
- Advisor(s): Muotri, Alysson R
- et al.
Microglia, the tissue-resident macrophages of the central nervous system (CNS), are the first line of defense against injury and disease. Given their unique ontology and context-specific functions, they might play key roles during neurodevelopment. Rett syndrome (RTT) is a progressive neurodevelopmental disorder characterized by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, whereupon affected patients can develop a range of behavioral and neurological symptoms. Although MECP2 is expressed in many different cell types, RTT is attributed to cell autonomous effects from a primary neuronal dysfunction. The role of microglia in RTT pathology has been studied with an ongoing controversy in mouse models. Here, we aim to decipher if human microglia have an impact in RTT pathogenesis by using induced-pluripotent stem cells (iPSCs). We utilized high throughput, multiplex experiments in a holistic approach to investigate the inflammatory signature of RTT microglia in gene expression and cytokine release. Consequentially, we observed genes differentially expressed in RTT microglia with no clear inflammatory phenotype. Additionally, we observed a significant decrease in RTT microglia’s phagocytic ability, congruent with our gene expression analysis. Finally, we increased the complexity of our model by establishing a neuron-microglia co-culture system to study the impact of microglia on neuronal synaptogenesis in both healthy and RTT conditions. Altogether, our data suggests that the lack of MECP2 in microglial cells alters its functions, which might be implicated in RTT pathogenesis and that they can potentially be targeted to develop novel therapies for RTT patients for whom there is currently no cure.