Publisher：Cold Spring Harbor Laboratory  

Abstract

Microglia, resident immune cells in the central nervous system, undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial development and maturation remain largely unknown. In this study, we show that neuronal micronuclei propagate microglia, followed by changing microglial states during the postnatal period. We discovered that neurons passing through a dense region of the developing neocortex give rise to micronuclei and release them into the extracellular space. Moreover, neuronal micronuclei were incorporated into microglia and affected morphological changes. Loss of thecGASgene alleviates effects on micronucleus-dependent morphological changes. Notably, neuronal micronuclei-harboring microglia exhibit unique transcriptome signatures. These results demonstrate that neuronal micronuclei serve as niche signals that produce novel microglial states. Our findings provide a potential mechanism for regulating the microglial state in the early-postnatal neocortex.

DOI： 10.1101/2023.07.31.551211

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Microglia are the resident immune cells of the central nervous system (CNS). Microglia originate from erythromyeloid progenitors in the yolk sac at the early embryonic stage, and these progenitors then colonize the CNS through extensive migration and proliferation during development. Microglia account for 10% of all cells in the adult brain, whereas the proportion of these cells in the embryonic brain is only 0.5–1.0%. Nevertheless, microglia in the developing brain widely move their cell body within the structure by extending filopodia; thus, they can interact with surrounding cells, such as neural lineage cells and vascular-structure-composing cells. This active microglial motility suggests that embryonic microglia play a pivotal role in brain development. Indeed, recent increasing evidence has revealed diverse microglial functions at the embryonic stage. For example, microglia control differentiation of neural stem cells, regulate the population size of neural progenitors and modulate the positioning and function of neurons. Moreover, microglia exert functions not only on neural lineage cells but also on blood vessels, such as supporting vascular formation and integrity. This review summarizes recent advances in the understanding of microglial cellular dynamics and multifaceted functions in the developing brain, with particular focus on the embryonic stage, and discusses the fundamental molecular mechanisms underlying their behavior.

DOI： 10.3389/fncel.2023.988952

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.celrep.2023.112092

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neures.2022.09.006

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/life12111835

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Authorship：Corresponding author   Publisher：Cold Spring Harbor Laboratory  

Summary

The relationships between microglia and macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated labeling, we found that a group of intraventricular macrophages belonging to border-associated macrophages (BAMs), which were abundantly observed along the inner surface of the mouse cerebral wall at embryonic day 12, frequently entered the brain wall. Immunohistochemistry of the tracked cells showed that postinfiltrative BAMs acquired microglial properties while losing a macrophage phenotype. We also found that the intraventricular BAMs were supplied transepithelially from the roof plate. Thus, this study demonstrates that the “roof plate→ventricle→cerebral wall” route is an essential path for microglial colonization into the embryonic mouse brain.

DOI： 10.1101/2022.07.27.501563

Language：English   Publisher：Science Advances  

While amyloid-β lies upstream of tau pathology in Alzheimer’s disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

DOI： 10.1126/sciadv.abm5029

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/sciadv.abm5029.

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

DOI： 10.1523/JNEUROSCI.1201-21.2021

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Language：English   Publisher：Anatomical Science International  

Microglia are the resident immune cells of the central nervous system. Microglial progenitors are generated in the yolk sac during the early embryonic stage. Once microglia enter the brain primordium, these cells colonize the structure through migration and proliferation during brain development. Microglia account for a minor population among the total cells that constitute the developing cortex, but they can associate with many surrounding neural lineage cells by extending their filopodia and through their broad migration capacity. Of note, microglia change their distribution in a stage-dependent manner in the developing brain: microglia are homogenously distributed in the pallium in the early and late embryonic stages, whereas these cells are transiently absent from the cortical plate (CP) from embryonic day (E) 15 to E16 and colonize the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ). Previous studies have reported that microglia positioned in the VZ/SVZ/IZ play multiple roles in neural lineage cells, such as regulating neurogenesis, cell survival and neuronal circuit formation. In addition to microglial functions in the zones in which microglia are replenished, these cells indirectly contribute to the proper maturation of post-migratory neurons by exiting the CP during the mid-embryonic stage. Overall, microglial time-dependent distributional changes are necessary to provide particular functions that are required in specific regions. This review summarizes recent advances in the understanding of microglial colonization and multifaceted functions in the developing brain, especially focusing on the embryonic stage, and discuss the molecular mechanisms underlying microglial behaviors.

DOI： 10.1007/s12565-021-00631-w

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Language：Japanese   Publisher：公益社団法人 日本薬学会  

脳には、神経系の細胞の他にも免疫細胞であるミクログリアが存在し、脳の機能を支えている。ミクログリアは胎生期から神経系細胞の分化や配置を制御し、脳発達に貢献していることが明らかにされつつある。胎生期の大脳実質において、ミクログリアは胎齢の進行に伴い分布を変化させる。本稿では、最近筆者らが報告したマウス胎生期の大脳実質内におけるミクログリアの移動メカニズムと、その生理学的意義についての研究内容を中心に紹介する。

DOI： 10.14894/faruawpsj.58.9_868

CiNii Research

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Microglia, despite their extensive surveying activity, temporarily disappear from the midembryonic CP. However, the mechanism and significance of this absence are unknown. Here, we show that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and subventricular zone and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-grown CP neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that "sanctuarization" from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.

DOI： 10.1038/s41467-020-15409-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Development Growth and Differentiation  

Morphogenesis and organ development should be understood based on a thorough description of cellular dynamics. Recent studies have explored the dynamic behaviors of mammalian neural progenitor cells (NPCs) using slice cultures in which three-dimensional systems conserve in vivo-like environments to a considerable degree. However, live observation of NPCs existing truly in vivo, as has long been performed for zebrafish NPCs, has yet to be established in mammals. Here, we performed intravital two-photon microscopic observation of NPCs in the developing cerebral cortex of H2B-EGFP or Fucci transgenic mice in utero. Fetuses in the uterine sac were immobilized using several devices and were observed through a window made in the uterine wall and the amniotic membrane while monitoring blood circulation. Clear visibility was obtained to the level of 300 μm from the scalp surface of the fetus, which enabled us to quantitatively assess NPC behaviors, such as division and interkinetic nuclear migration, within a neuroepithelial structure called the ventricular zone at embryonic day (E) 13 and E14. In fetuses undergoing healthy monitoring in utero for 60 min, the frequency of mitoses observed at the apical surface was similar to those observed in slice cultures and in freshly fixed in vivo specimens. Although the rate and duration of successful in utero observations are still limited (33% for ≥10 min and 14% for 60 min), further improvements based on this study will facilitate future understanding of how organogenetic cellular behaviors occur or are pathologically influenced by the systemic maternal condition and/or maternal-fetal relationships.

DOI： 10.1111/dgd.12648

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Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1523/ENEURO.0312-18.2018

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/gtc.12632

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Language：English   Publishing type：Research paper (scientific journal)  

In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFRβ antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.

DOI： 10.1172/jci.insight.90905

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Language：Japanese   Publisher：Japan Health Physics Society  

DOI： 10.5453/jhps.50.111

CiNii Research

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Background: A host receptor has not yet been identified for glycerol monomycolate (GroMM), an immunostimulatory lipid of mycobacteria. Results: GroMM recognition occurred in cell transfectants expressing human, but not mouse Mincle. Human Mincle transgenic mice acquired the ability to respond to GroMM. Conclusion: GroMM is a ligand for human Mincle. Significance: The molecular basis underlying the innate immune recognition of GroMM has been elucidated.
An array of lipidic compounds that constitute the cell wall of mycobacteria is recognized by host receptors. Examples include trehalose dimycolate (TDM), which is a major surface-exposed glycolipid of mycobacteria, that interacts with the macrophage inducible C-type lectin, Mincle, and exerts its highly potent adjuvant functions. Recent evidence has suggested that glycerol monomycolate (GroMM), another mycolate-containing lipid species produced by mycobacteria, can stimulate innate immune cells; however, its specific host receptors have yet to be identified. We here demonstrated that cell transfectants expressing human Mincle (hMincle) reacted to both TDM and GroMM, while those expressing mouse Mincle (mMincle) only reacted to TDM and failed to recognize GroMM. Studies using domain swap chimeras confirmed that the ectodomain of hMincle, but not that of mMincle, interacted with GroMM, and site-directed mutagenesis analyses revealed that short stretches of amino acid residues at positions 174-176 and 195-196 were involved in GroMM recognition. To further substantiate the differential recognition of GroMM by hMincle and mMincle, hMincle transgenic/mMincle knock-out mice (i.e. hMincle(+) mice) were established and compared with non-transgenic mice (i.e. mMincle(+) mice). We showed that macrophages derived from hMincle(+) mice were activated by GroMM and produced inflammatory cytokines, whereas those derived from mMincle(+) mice did not exhibit any reactivity to GroMM. Furthermore, local inflammatory responses were elicited in the GroMM-injected skin of hMincle(+), but not mMincle(+) mice. These results demonstrated that GroMM is a unique ligand for hMincle that is not recognized by mMincle.

DOI： 10.1074/jbc.M114.566489

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Trehalose 6,6'-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-gamma, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.10.021

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Human CD1b molecules contain a maze of hydrophobic pockets and a tunnel capable of accommodating the unusually long, branched acyl chain of mycolic acids, an essential fatty acid component of the cell wall of mycobacteria. It has been accepted that CD1b-bound mycolic acids constitute a scaffold for mycolate-containing (glyco) lipids stimulating CD1b-restricted T cells. Remarkable homology in amino acid sequence is observed between human and monkey CD1b molecules, and indeed, monkey CD1b molecules are able to bind glucose monomycolate (GMM), a glucosylated species of mycolic acids, and present it to specific human T cells in vitro. Nevertheless, we found, unexpectedly, that Mycobacterium bovis bacillus Calmette-Guerin (BCG)-vaccinated monkeys exhibited GMM-specific T cell responses that were restricted by CD1c rather than CD1b molecules. GMM-specific, CD1c-restricted T cells were detected in the circulation of all 4 rhesus macaque monkeys tested after but not before vaccination with BCG. The circulating GMM-specific T cells were detected broadly in both CD4(+) and CD8(+) cell populations, and upon antigenic stimulation, a majority of the GMM-specific T cells produced both gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), two major host protective cytokines functioning against infection with mycobacteria. Furthermore, the GMM-specific T cells were able to extravasate and approach the site of infection where CD1c(+) cells accumulated. These observations indicate a previously inconceivable role for primate CD1c molecules in eliciting T cell responses to mycolate-containing antigens.

DOI： 10.1128/IAI.00871-12

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/jid.2011.280

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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