Role of CYFIP family proteins in brain development and neurological diseases
Year: 2026
Type: dissertation
Abstract: The Cytoplasmic FMR1-interacting proteins (CYFIP1/2) are integral components of the WAVE regulatory complex that act as internal regulators of actin dynamics, synaptic development, and neuronal plasticity. Genetic studies have linked CYFIP1 haploinsufficiency to schizophrenia (SCZ) and CYFIP2 missense mutations, such as R87C, to early-onset epileptic encephalopathy, yet the cellular mechanisms remain poorly understood. This thesis employed cellular and molecular biological techniques (immunohistochemistry, immunocytochemistry, neuronal culture, and plasmid cloning) and biochemical approaches (Western blotting and proteomics) to dissect CYFIP1/2 function in neurons and microglia. In Cyfip1 NEX-cKO middle-aged mice, neuronal and microglial populations were unaltered, with no compensatory upregulation of Cyfip2. Nevertheless, CA1 dendritic spine morphology was altered, and cortical excitatory/inhibitory synaptic protein levels were dysregulated, with mass spectrometry revealing additional hippocampal protein changes. In contrast, Cyfip1 microglial cKO (MG-cKO) reduced microglial complexity, enhanced phagocytosis and inflammation, and transcriptomic profiling revealed suppression of immune pathways with increased neuronal expression of NRGN in cortex. In parallel, wild-type CYFIP2 and its pathogenic mutant R87C were cloned and functionally analysed in neuronal cultures. CYFIP2 R87C did not affect early axon elongation but significantly enhanced dendritic arborisation, increased spine density, and elevated Homer1 intensity at synapses, indicating that this mutation augments neuronal structural complexity and synaptic protein enrichment. Together, these findings define distinct but converging roles of CYFIP1 and CYFIP2 in regulating neuronal and microglial morphology, synaptic protein expression, and actin-dependent plasticity, providing mechanistic insights into CYFIP dysfunction in diseases.
Author: Pei, Jiaxin
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221500924