@article{93fe1b7d9aa34608b138eb754db4ebe1,
title = "Abnormal microglia and enhanced inflammation-related gene transcription in mice with conditional deletion of Ctcf in Camk2a-Cre-expressing neurons",
abstract = "CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. CtcfloxP/loxP;Camk2a-Cre (Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immuno-staining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.",
keywords = "Behavior, CTCF, Chemokine, Dendritic spine, Inflammation, Microglia",
author = "McGill, {Bryan E.} and Barve, {Ruteja A.} and Maloney, {Susan E.} and Amy Strickland and Nicholas Rensing and Wang, {Peter L.} and Michael Wong and Richard Head and Wozniak, {David F.} and Jeffrey Milbrandt",
note = "Funding Information: Grant NCI P30CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences/ Clinical and Translational Science Award Grant UL1TR000448 from the National Center for Research Resources, a componentoftheNIH,andtheNIHRoadmapforMedicalResearch);theAlvinJ.SitemanCancerCenteratWashing-tonUniversitySchoolofMedicineandBarnes-JewishHospitalinSt.Louis,Missouri,fortheuseoftheSitemanFlow Cytometry facility, which provided training and access to the flow cytometer and analysis software (the Siteman CancerCenterissupportedinpartbyNCICancerCenterSupportGrantP30CA091842);theHopeCenterAlafiNeuro-imaging Laboratory (funded by NIH Shared Instrumentation Grant S10RR027552); and the Intellectual and Developmental Disabilities Research Center at Washington University (funded by the Eunice Kennedy Shriver National Funding Information: This work was supported by the National Institutes of Health (NIH Neurological Sciences Academic Development Grants K12NS001690 and T32NS007205 to B.E.M. and Grants RO1AG013730 and RO1NS087632 to J.M.). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis (the Center is partially supported by National Cancer Institute Cancer Center Support Grant NCI P30CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences/ Clinical and Translational Science Award Grant UL1TR000448 from the National Center for Research Resources, a component of the NIH, and the NIH Roadmap for Medical Research); the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Siteman Flow Cytometry facility, which provided training and access to the flow cytometer and analysis software (the Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant P30CA091842); the Hope Center Alafi Neuroimaging Laboratory (funded by NIH Shared Instrumentation Grant S10RR027552); and the Intellectual and Developmental Disabilities Research Center at Washington University (funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH Grant U54HD087011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 the authors.",
year = "2018",
month = jan,
day = "3",
doi = "10.1523/JNEUROSCI.0936-17.2017",
language = "English",
volume = "38",
pages = "200--219",
journal = "Journal of Neuroscience",
issn = "0270-6474",
number = "1",
}