The cytoskeleton as a signaling node that contributes to microglia activation and diversity
Subject Area
Immunology
Experimental Models for the Understanding of Nervous System Diseases
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500299518
Microglia change their morphology under inflammatory conditions by cytoskeletal changes. We recently found evidence for a reverse relationship between inflammation and cytoskeletal changes: A targeted deletion of the cytoskeleton-regulatory factor CYFIP1 in microglia not only leads to changes in microglial morphology but also to a pronounced microglial inflammatory state. CYFIP1 and another microglial gene that is involved in actin cytoskeleton regulation - ABI3 - have been implicated as risk genes in Alzheimer’s disease and neurodevelopmental diseases such as autism and schizophrenia.This suggests that the cytoskeleton may contribute to microglial activation in neurological disease.Thus, in this project we aim to study how CYFIP1 and other actin cytoskeleton pathways modulate microglial activation, and identify involved innate immune pathways and cellular mechanisms. Furthermore, we will characterize the role of microglial CYFIP1 in CNS and synapse integrity under physiological condition and upon maternal immune activation (MIA) in vivo. We will also link these findings to published data from autism and Alzheimer’s disease patients.We plan to employ state-of-the-art experimental methods including conditional mouse models, 3D murine primary and human iPSC-derived microglia cultures, human post-mortem CNS tissue, optogenetic modulation of the cytoskeleton and transcriptomic and epigenetic profiling.
DFG Programme
Priority Programmes
