Ricerc@Sapienza

Fragile X syndrome (FXS) is the most common inherited form of human mental retardation, and it is caused by expansion of CGG repeat in the FMR1 gene. The resulting epigenetic silencing causes the loss of the fragile X mental retardation protein (FMRP) with defects in the regulation of dendritic spine morphology and synaptogenesis.
FXS is widely studied into 2D cell culture differentiating human iPSCs into neuronal population to characterize the disease phenotype taking advantages of molecular and functional analysis. However, conventional 2D cell culture fails to recapitulate the complex neural environment revealing itself as a not reliable in vitro model system to fully characterize the pathology. In this direction novel 2D and 3D model systems have been proposed for dissecting the molecular and cellular processes underling FXS.
Several 3D protocols are available to better mimicking the cell complexity and architecture of the brain tissue, however the lack of non-neural cell types such as microglia still hinders their exploitation for the study of the neuro-immune axis in neurodevelopmental diseases.

The aim of our study is to create an in vitro 3D model based on patient-specific induced pluripotent stem cells (iPSCs) with the purpose of deciphering the neurobiological phenotypes associated with FXS. Specifically, we propose to co-culture iPSC-derived dorso-cortical organoids and isogenic iPSC-derived microglia to generate a disease-relevant and tailored platform for the investigation of neuro-immune interaction during brain development. Indeed, microglia plays a prominent role in shaping synaptic circuitries during neurodevelopment and its presence might unveil possible neural-immune interplay at the basis of FXS and the establishment of a mature synaptic transmission.