Language：English   Publisher：Life  

In the capillary walls, vascular endothelial cells are covered with mural cells, such as smooth muscle cells and pericytes. Although pericytes had been thought to play simply a structural role, emerging evidence has highlighted their multiple functions in the embryonic, postnatal, and adult brain. As the central nervous system (CNS) develops, the brain’s vascular structure gradually matures into a hierarchical network, which is crucial for the proper development of neural lineage cells by providing oxygen and nutrients. Pericytes play an essential role in vascular formation and regulate blood‒brain barrier (BBB) integrity as a component of the neurovascular unit (NVU), in collaboration with other cells, such as vascular endothelial cells, astrocytes, neurons, and microglia. Microglia, the resident immune cells of the CNS, colonize the brain at embryonic day (E) 9.5 in mice. These cells not only support the development and maturation of neural lineage cells but also help in vascular formation through their extensive migration. Recent studies have demonstrated that pericytes directly contact microglia in the CNS, and their interactions have a profound effect on physiological and pathological aspects. This review summarizes the function of pericytes, focusing on the interplay between pericytes and microglia.

DOI： 10.3390/life12111835

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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   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

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)  

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

DOI： 10.1523/ENEURO.0312-18.2018

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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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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)  

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

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)  

Event date： 2021.2

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Event date： 2020.9

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2020.9

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2020.1

Language：English   Presentation type：Oral presentation (general)  

Event date： 2019.7

Language：English   Presentation type：Poster presentation  

Event date： 2018.2

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Event date： 2017.3

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Poster presentation  

Language：Japanese   Presentation type：Poster presentation  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Poster presentation