Abstract
The micronucleus is known to be a biomarker for genomic instability, which is a hallmark of tumors and aging. Normally, micronuclei are produced by segregation errors and mechanical stresses arising from dividing or migrating cells, leading to activation of the innate immune response pathway. Although micronuclei often emerge in damaged tissues, the quantitative procedure for analyzing micronuclei accurately has been problematic. Here, we introduce a novel MATLAB-based program for quantifying micronuclei (CAMDi: calculating automatic micronuclei distinction) in vitro and in vivo. CAMDi is adaptable to various experimental imaging techniques and is useful for obtaining reproducible data. CAMDi enables us to measure the accurate size of micronuclei from the three-dimensional images. Using CAMDi, we revealed a novel link between the emergence of micronuclei and neuroinflammation. We found that inflammatory stimulation does not increase the number of micronuclei in primary neurons. On the other hand, the administration of lipopolysaccharide into mice slightly increases micronuclei formation in neurons of the hippocampus region. These findings demonstrate that neuronal micronuclei formations are induced by an inflammatory response in a non-cell-autonomous manner. We provide a novel tool, CAMDi, to quantify micronuclei and demonstrate that neuronal micronuclei are produced not only by the cell-autonomous process but also by the intercellular communication associated with neuroinflammation in vivo.
Highlights
The micronucleus is known to be a biomarker for genomic instability, which is a hallmark of tumors and aging
The damaged nuclei are repaired by the endosomal sorting complexes required for transport (ESCRT) III complex after rupturing the nuclear envelope, some nuclear components leak into the cytoplasm[12,13]
Because the micronuclei emerge in various tissues in response to genotoxic s timulation[8], we investigated whether the micronuclei are observed in the wildtype tissues, such as the heart, skeletal muscle, testis, kidney, spleen, and thymus
Summary
The micronucleus is known to be a biomarker for genomic instability, which is a hallmark of tumors and aging. Stimulation with cytokinesis-related inhibitors, such as paclitaxel, promotes abnormal nuclei formations in vitro and in vivo[7,8] These reagents frequently induce the mis-segregation of sister chromatids by inhibiting. Treatment with genotoxic reagents, such as etoposide, methanesulfonate, and bleomycin, results in micronuclei formation[10] Since these reagents often hamper DNA repair and replication, stimulating cells with these reagents damages chromosomes. The nuclear deformation and envelope rupture elicited by physical stress frequently causes micronuclear production Since these micronuclei are non-essential components in cells, they are usually cleared by the autophagy pathway to maintain an intracellular environment. Since excess inflammation, which is frequently observed in the neurodegenerative brain, causes DNA damage in tumor cells, neuroinflammation could be a potential trigger that induces micronuclei formation in the b rain[22]
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