Project Details
Projekt
Neural network assembly in Fragile X syndrome
Applicant
Dr. Sara Brignani, Ph.D.
Subject Area
Experimental Models for the Understanding of Nervous System Diseases
Developmental Neurobiology
Developmental Neurobiology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 524585667
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the major monogenetic cause of autism spectrum disorder. FXS is caused by the epigenetic inactivation of the FMR1 gene at approximately 10 weeks of gestation. FMR1 encodes for the fragile X mental retardation protein (FMRP), which regulates the translation of mRNAs involved in brain development. Already at 6 months of age, FXS infants display structural alterations in several brain areas, including the prefrontal-striatal circuit, suggesting an altered neural network assembly during foetal brain development. This project aims at understanding the causal factors of the altered assembly of the prefrontal-striatal circuit in FXS foetuses. To achieve this goal, I will generate human cortical and striatal organoids from FXS naïve induced pluripotent stem cells, and assemble these organoids into cortico-striatal assembloids, which will allow to investigate key features in FXS pathogenesis with unprecedented accuracy. The resulting in vitro models will be used to conduct research in two directions. First, it will allow me to recapitulate cortico-striatal circuit assembly in FXS, identifying potential defects in neurogenesis and gliogenesis, neuron morphology, axon growth and guidance, and neural connections. Second, I will investigate the molecular causes of these defects, in particular how the absence of FMRP affects the expression of proteins involved in the assembly of the FXS cortico-striatal circuit. These studies will pave the way for the identification of new therapeutic strategies to prevent the development of the disease.
DFG Programme
WBP Fellowship
International Connection
Italy
