Projektbeschreibung
Wie die Dynamik des MECP2-Gens Gehirnfunktionen beeinflusst
Epigenetische Prozesse sind für komplexe Gehirnfunktionen unerlässlich. Gestörte epigenetische Signale könnten zu verheerenden Gehirnpathologien wie dem Rett-Syndrom führen – einer postnatalen neurologischen Entwicklungsstörung, die zu einer raschen Verschlechterung der sensorischen, motorischen, kognitiven und sozialen Funktionen führt. Das Rett-Syndrom wird durch Mutationen auf dem X-Chromosom an einem Gen namens MECP2 verursacht. Im Rahmen des EU-finanzierten Projekts 2CE MECP2 wird ein bildgebender Ansatz zur Überwachung der endogenen MeCP2-Signalgebung und -Dynamik in intakten neuronalen Schaltkreisen bei Mäusen entwickelt. Mithilfe von Genomeditierung und Fluoreszenz-Bildgebungsverfahren werden die Forschenden die MeCP2-Aktivität im intakten Mäusegehirn über Zelltypen, Schaltkreise und sensorische Erfahrungen hinweg kartieren.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesphysical sciencesopticsmicroscopyfluorescence lifetime imaging
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesgeneticsepigenetics
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
69978 Tel Aviv
Israel