1.CXCR5 Regulates Neuronal Polarity Development and Migration in the Embryonic Stage via F-Actin Homeostasis and Results in Epilepsy-Related Behavior.
Zhijuan ZHANG ; Hui ZHANG ; Ana ANTONIC-BAKER ; Patrick KWAN ; Yin YAN ; Yuanlin MA
Neuroscience Bulletin 2023;39(11):1605-1622
Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.
Animals
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Humans
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Mice
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Actin Cytoskeleton/metabolism*
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Actins/metabolism*
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Epilepsy/metabolism*
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Neurons/metabolism*
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Receptors, CXCR5/metabolism*
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Seizures/metabolism*
2.Phenotypic Tfh development promoted by CXCR5-controlled re-localization and IL-6 from radiation-resistant cells.
Xin CHEN ; Weiwei MA ; Tingxin ZHANG ; Longyan WU ; Hai QI
Protein & Cell 2015;6(11):825-832
How follicular T-helper (Tfh) cells develop is incompletely understood. We find that, upon antigen exposure in vivo, both naïve and antigen-experienced T cells sequentially upregulate CXCR5 and Bcl6 within the first 24 h, relocate to the T-B border, and give rise to phenotypic Bcl6(+)CXCR5(+) Tfh cells before the first cell division. CXCR5 upregulation is more dependent on ICOS costimulation than that of Bcl6, and early Bcl6 induction requires T-cell expression of CXCR5 and, presumably, relocation toward the follicle. This early and rapid upregulation of CXCR5 and Bcl6 depends on IL-6 produced by radiation-resistant cells. These results suggest that a Bcl6(hi)CXCR5(hi) phenotype does not automatically define a Tfh lineage but might reflect a state of antigen exposure and non-commitment to terminal effector fates and that niches in the T-B border and/or the follicle are important for optimal Bcl6 induction and maintenance.
Animals
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CD40 Ligand
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metabolism
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Cell Differentiation
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physiology
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DNA-Binding Proteins
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metabolism
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Inducible T-Cell Co-Stimulator Protein
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metabolism
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Interleukin-6
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metabolism
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Mice
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Proto-Oncogene Proteins c-bcl-6
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Receptors, CXCR5
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metabolism
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T-Lymphocytes, Helper-Inducer
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metabolism