Study on the Propagation of Neuronal Micronuclei Regulating Microglial Characteristics

Academic Background

Microglia, the resident immune cells in the central nervous system (CNS), play a crucial role in maintaining brain homeostasis, regulating neuronal development, synaptic pruning, and responding to pathological states. However, despite extensive research on microglial functions, the microenvironmental signals underlying their differentiation and maturation remain unclear. In particular, the mechanisms by which microglia alter their morphology and functions in response to local environmental signals have not been fully elucidated.

In this context, researchers proposed a novel hypothesis: neuronal micronuclei (MN) might act as signaling molecules to regulate microglial characteristics and functions. Micronuclei are small nuclear structures resulting from chromosome segregation errors or physical stress during cell division, typically associated with cancer and genomic instability. However, the role of micronuclei in physiological conditions, especially in intercellular communication between neurons and microglia, has not been thoroughly investigated.

Source of the Paper

This study was led by a research team from the University of Tsukuba, Japan, with primary authors including Sarasa Yano and Natsu Asami. The findings were published in Nature Neuroscience in 2025. The research received support from multiple Japanese research institutions and universities, including the University of Tokyo and Nagoya University.

Research Process and Results

1. Generation and Release of Neuronal Micronuclei

The study first explored the mechanisms of micronuclei generation in neurons. By observing embryonic mouse brains, researchers found that micronuclei primarily existed in the superficial layers of the cerebral cortex (e.g., the marginal zone and primitive cortical zone). Further experiments revealed that neurons passing through narrow regions during migration experienced physical stress, leading to nuclear membrane deformation and micronuclei formation. To validate this mechanism, the research team designed in vitro experiments simulating neurons passing through narrow pores and observed a significant increase in micronuclei. Additionally, inhibiting autophagy (via Atg7 gene knockout) delayed micronuclei clearance, further supporting the hypothesis that micronuclei generation is related to physical stress.

2. Transfer of Micronuclei to Microglia

Next, the research team investigated whether micronuclei could be transferred from neurons to microglia. Using genetic editing techniques, researchers created a mouse model specifically labeling neuronal nuclear membranes and observed the persistent presence of micronuclei in postnatal mouse brains. Further experiments demonstrated that micronuclei were released into the extracellular space and subsequently taken up by microglia. In vitro experiments also confirmed that microglia efficiently incorporated micronuclei released by neurons, leading to morphological changes post-uptake.

3. Effects of Micronuclei on Microglial Morphology and Function

Using two-photon microscopy, the research team observed that microglia incorporating micronuclei tended to slowly retract their processes. Additionally, RNA sequencing analysis revealed that microglia with micronuclei exhibited unique transcriptomic signatures, particularly upregulation of extracellular matrix (ECM)-related genes. These results indicated that micronuclei not only influenced microglial morphology but also potentially regulated their functions by altering gene expression patterns.

4. Role of cGAS in Micronuclei-Dependent Morphological Changes

Upon the release of chromatin DNA from micronuclei within cells, the cGAS-STING pathway is activated, triggering an innate immune response. To validate this mechanism, the research team analyzed cGAS knockout mouse brains and found that cGAS deficiency alleviated the effects of micronuclei on microglial morphological changes. This suggested that cGAS plays a significant role in the regulation of microglial characteristics by micronuclei.

Research Conclusion

This study was the first to reveal the critical role of neuronal micronuclei as intercellular signaling molecules in physiological conditions. By regulating microglial morphology and gene expression, micronuclei influenced their functions during early developmental stages. This discovery not only deepens our understanding of microglial regulatory mechanisms but also provides new potential targets for the treatment of neurological disorders.

Research Highlights

1. Discovery of a New Mechanism: First to uncover the role of neuronal micronuclei in intercellular communication between neurons and microglia.
2. Innovative Experimental Methods: Utilized a variety of techniques, including genetic editing, two-photon microscopy imaging, and RNA sequencing, to comprehensively analyze the generation, transfer, and effects of micronuclei on microglia.
3. Potential Application Value: The findings offer new insights into the treatment of neurological disorders (e.g., neurodegenerative diseases), particularly through modulating the cGAS-STING pathway to intervene in microglial functions.

Other Valuable Information

The study also found that the generation and release of micronuclei might be closely related to autophagy and lysosomal functions. Future research could further explore the role of the autophagy pathway in micronuclei secretion and how micronuclei regulate microglial functions through the cGAS-STING pathway.

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This study not only provides new perspectives on understanding microglial regulatory mechanisms but also offers potential new targets for the treatment of neurological disorders. By revealing the critical role of neuronal micronuclei in intercellular communication, this research opens new directions for future neuroscience studies.