Project description
Research deciphers how MECP2 gene dynamics affect brain functions
Epigenetic processes are essential for complex brain functions. Disrupted epigenetic signals could lead to devastating brain pathologies such as Rett syndrome – a postnatal neurodevelopmental disease causing rapid deterioration of sensory, motor, cognitive and social functions. Rett syndrome is caused by mutations of the X chromosome on a gene called MECP2. The EU-funded 2CE MECP2 project will develop an imaging-based approach to monitor endogenous MeCP2 signalling and dynamics in intact neuronal circuits in mice. Using genome editing and fluorescence imaging techniques, the researchers will map MeCP2 activity in the intact mouse brain across cell types, circuits and sensory experiences.
Objective
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.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering sensors biosensors
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2021-STG
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69978 Tel Aviv
Israel
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