Background: The CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood.
Methods: We generated multiple CRISPR (clustered regularly interspaced short palindromic repeat) knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human induced pluripotent stem cell (iPSC)-derived neuronal cultures as an in vitro model of synaptic pruning. We repeated these analyses in human iPSC-derived microglia-like cells derived from 3 isogenic wild-type/knockout line pairs derived from 2 donors and further characterized microglial development and function through morphology and motility.
Results: CYFIP1 knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with a statistically significant decrease in synaptic vesicle phagocytosis in microglia-like cell models derived from both peripheral blood mononuclear cells and iPSCs. Morphology was also shifted toward a more ramified profile, and motility was significantly reduced. However, iPSC-CYFIP1 knockout lines retained the ability to differentiate to functional microglia.
Conclusions: The changes in microglial phenotype and function due to the loss of function of CYFIP1 observed in this study implicate a potential impact on processes such as synaptic pruning that may contribute to CYFIP1-related neurodevelopmental disorders. Investigating risk genes in a range of central nervous system cell types, not solely neurons, may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874584 | PMC |
| http://dx.doi.org/10.1016/j.biopsych.2023.07.022 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Ultrastructural Study and Immunohistochemical Characteristics of Mesencephalic Tegmentum in Juvenile Chum Salmon () Brain After Acute Traumatic Injury.
Int J Mol Sci
January 2025
A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, 690041 Vladivostok, Russia.
The ultrastructural organization of the nuclei of the tegmental region in juvenile chum salmon () was examined using transmission electron microscopy (TEM). The dorsal tegmental nuclei (DTN), the nucleus of (NFLM), and the nucleus of the oculomotor nerve (NIII) were studied. The ultrastructural examination provided detailed ultrastructural characteristics of neurons forming the tegmental nuclei and showed neuro-glial relationships in them.
View Article and Find Full Text PDFEarly precursor-derived pituitary gland tissue-resident macrophages play a pivotal role in modulating hormonal balance.
Cell Rep
January 2025
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland. Electronic address:
The pituitary gland is the central endocrine regulatory organ producing and releasing hormones that coordinate major body functions. The physical location of the pituitary gland at the base of the brain, though outside the protective blood-brain barrier, leads to an unexplored special immune environment. Using single-cell transcriptomics, fate mapping, and imaging, we characterize pituitary-resident macrophages (pitMØs), revealing their heterogeneity and spatial specialization.
View Article and Find Full Text PDFTransformation of brain myeloid cell populations by SIV in rhesus macaques revealed by multiomics.
Commun Biol
January 2025
Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we perform single-cell multiomic sequencing, including gene expression and ATAC-seq, on myeloid cells from the brains of rhesus macaques with SIV-induced encephalitis (SIVE) as well as uninfected controls.
View Article and Find Full Text PDFDistinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines.
Cells
December 2024
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain.
Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a.
View Article and Find Full Text PDFIdentification of EcoHIV-Infected Cells in Microglia-Manipulated Transgenic Mice.
J Vis Exp
December 2024
Cognitive and Neural Sciences, Department of Psychology, University of South Carolina;
Article Synopsis
- Combined antiretroviral therapy (cART) has significantly enhanced the quality of life for people living with HIV (PLWH), but many older adults face HIV-associated neurocognitive disorders (HAND).
- A new biological model using chimeric HIV (EcoHIV) has been developed in rats to study the neurological effects of HIV, but understanding its distribution in the brain remains a challenge.
- In this study, EcoHIV was modified and injected into mice to investigate whether microglia are the primary cells containing HIV; results show that microglia are indeed the main reservoirs for HIV in the brain, highlighting the model's potential for exploring neurocognitive disorders.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!