Descrizione del progetto
Una ricerca decifra il modo in cui le dinamiche del gene MECP2 influenzano le funzioni cerebrali
I processi epigenetici sono essenziali per le complesse funzioni cerebrali. L’interruzione dei segnali epigenetici potrebbe portare a patologie cerebrali devastanti come la sindrome di Rett, un disturbo dello sviluppo neurologico postnatale che provoca un rapido deterioramento delle funzioni sensoriali, motorie, cognitive e sociali. La sindrome di Rett è causata da mutazioni del cromosoma X su un gene chiamato MECP2. Il progetto 2CE MECP2, finanziato dall’UE, svilupperà un approccio basato sull’imaging per monitorare le dinamiche e la segnalazione endogena di MeCP2 nei circuiti neuronali intatti dei topi. Utilizzando tecniche di editing del genoma e di imaging a fluorescenza, i ricercatori mapperanno l’attività di MeCP2 nel cervello intatto del topo attraverso tipi cellulari, circuiti ed esperienze sensoriali.
Obiettivo
Epigenetic signalling pathways are required to translate external sensory input to neuronal gene modulation and function, and disruption of epigenetic signals leads to devastating brain pathologies. One prominent example is Rett syndrome (RTT), a postnatal neurodevelopmental disease which results in rapid deterioration of sensory, motor, cognitive, and social functions. RTT is caused by loss of function mutations in a single gene encoding for Methyl-CpG binding protein 2 (MeCP2), an abundant and multifunctional methylation reader in the brain. While transgenic mouse models of MeCP2 loss have provided significant insights into RTT, they also revealed the vast complexity of the regulation of MeCP2 signalling and cell- specific heterogeneity. Importantly both a deficit and a surplus of MeCP2 give rise to pathological phenotypes. Here, we will develop an imaging-based approach to monitor endogenous MeCP2 signalling and dynamics in intact neuronal circuits in awake behaving mice. We will combine CRISPR/Cas9 genome editing to fluorescently label endogenous MeCP2 with FRET based biosensors to detect dynamic MeCP2 signalling without perturbing its innate regulation. In vivo two-photon fluorescence lifetime imaging will enable dual imaging of MeCP2 signalling and concurrent neuronal activity. Using this approach, we will map the functional landscape of MeCP2 activity in the intact mouse brain across cell-type, circuit, and sensory experience. We will also image in vivo MeCP2 signalling in transgenic mice with common RTT mutations. This will allow us to detect early cell-type specific MeCP2 dysfunction and avoid broad late-stage RTT symptoms. The direct visualisation of the intricate interplay between MeCP2 signalling and neuronal function within intact neuronal circuits will be transformative since it will shed light on the physiological role of epigenetic signalling in the brain and provide vital insights to future therapeutic interventions.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesphysical sciencesopticsmicroscopyfluorescence lifetime imaging
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesgeneticsepigenetics
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
69978 Tel Aviv
Israele