Description du projet
Des recherches pour décrypter comment la dynamique du gène MECP2 affecte les fonctions cérébrales
Les processus épigénétiques sont essentiels aux fonctions complexes du cerveau. Des signaux épigénétiques perturbés pourraient conduire à des pathologies cérébrales dévastatrices telles que le syndrome de Rett, une maladie neurodéveloppementale postnatale entraînant une détérioration rapide des fonctions sensorielles, motrices, cognitives et sociales. Le syndrome de Rett est causé par des mutations du chromosome X sur un gène appelé MECP2. Le projet 2CE MECP2, financé par l’UE, développera une approche basée sur l’imagerie pour surveiller la signalisation et la dynamique de MeCP2 endogène dans des circuits neuronaux intacts chez la souris. À l’aide de techniques d’édition du génome et d’imagerie par fluorescence, les chercheurs cartographieront l’activité de MeCP2 dans le cerveau intact de la souris à travers les types de cellules, les circuits et les expériences sensorielles.
Objectif
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.
Champ scientifique
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesphysical sciencesopticsmicroscopyfluorescence lifetime imaging
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesgeneticsepigenetics
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitution d’accueil
69978 Tel Aviv
Israël