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Researchers at University of Tsukuba have discovered a novel mechanism involved in brain development. They found that small fragments called micronuclei produced by neuronal nuclei are released into the extracellular space during the early establishment of the postnatal brain. They also found that microglia, which are resident immune cells in the brain, incorporate these micronuclei, thereby altering gene expression patterns and microglial characteristics.

Tsukuba, Japan—The brains of mammals, including humans, not only contain neurons but also glial cells called microglia. Microglia modulate the immune response in the central nervous system, as well as various other functions, including neurogenesis, the formation of neural networks, and the control of cerebrovascular function. Recent findings have confirmed that postnatal microglia are not homogeneous cells but rather a heterogeneous population of cells that exhibit different gene expression patterns that vary with the surrounding environment in the brain. However, the detailed mechanisms by which microglia acquire new functions and change their properties have not been elucidated.

In this study, detailed observations of the embryonic mouse brain revealed that small nuclear fragments called micronuclei are produced and released into the extracellular space as neurons migrate to a predetermined position and begin to establish the brain. Microglia, which reside around neurons, take up the micronuclei and use an innate immune response pathway activated by DNA virus infection to alter microglial morphology. Furthermore, the uptake of micronuclei upregulates the expression of microglial genes involved in forming the extracellular matrix, the substance that fills the spaces between cells. Therefore, micronuclei in the extracellular space function as mediators that alter the properties of microglia.

Microglial subpopulations in the postnatal stage are significantly more heterogeneous than those in the adult stage and may be crucial for the functional regulation of cerebral blood vessels and the meninges. Further validation of the study findings would deepen our understanding of the structure and function of central nervous system interfaces, such as the meninges and blood vessels.

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This work was supported by Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan, JSPS KAKENHI [16KK0158 (F.T.), 20K05951 (F.T.), 23H04214 (Y.K.), 24K02020 (Y.K.), JP20H05688 (K.N.), JP22K19365 (K.N.), JSPS, Research Fellowship for Young Scientists (19J20619 (S.Y.), 23KJ0285(T.T.)], AMED PRIME [24028934 (F.T.)], Kao foundation for health science (F.T.), Gout and uric acid foundation (F.T.), Asahi Glass Foundation (Y.K.), and SECOM Science and Technology Foundation (Y.K.).

Original Paper

Title of original paper:

Propagation of neuronal micronuclei regulates microglial characteristics

Journal:

Nature Neuroscience

DOI:

10.1038/s41593-024-01863-5

Correspondence

Assistant Professor TSURUTA Fuminori
Institute of Life and Environmental Sciences, University of Tsukuba

Related Link

Institute of Life and Environmental Sciences