Reference:
GGP09117
Abstract:
Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. Mutations in the MECP2 gene have long represented the only known cause of Rett. Recently, we demonstrated that mutations in a different gene, FOXG1, are responsible for the most severe form of Rett, named congenital variant, in which girls present the same clinical features of classic Rett but they manifest symptoms since the very first months of life. FOXG1 encodes for a factor that regulates gene expression specifically in the brain. To uncover the molecular mechanisms causing congenital Rett, we will first evaluate whether FoxG1 and MeCP2 physically interact or at least participate in common molecular processes as suggested by the similarity of disease caused by mutations in the two genes. We will then identify genes showing altered expression as a consequence of FoxG1 reduction or absence in mouse brain. During embryonic development, Foxg1 has been implicated in regulating proliferation of progenitor cells. However, its persistent expression in post-natal brain suggests that it may exert important roles also in differentiating and mature neurons. To verify this hypothesis, we will reduce its expression in isolated mouse neurons and we will analyze the effects on their differentiation and establishment of connections. A human neuronal model will be also established by the new technique of ﾓgenetic reprogrammingﾔ that allows to obtain human ﾓaffectedﾔ neurons from patientsﾒ fibroblasts. These cells will be analyzed for survival, morphology and activity to ascertain how Foxg1 deficiency affects neurons. This could represent an optimal setting for investigation of the cellular defects causing the disease and for large-scale drug screenings aimed at evaluating new molecules.
PROJECT DETAILS
beginning: 2009.
end: 2012.
Country of research: Italy
Counry of funding source: Italy
Funding organization: Telethon
Financing: PRIVATE FUNDERS – 293 100 €