研究者詳細 - 宮田　卓樹

論文 - 宮田　卓樹

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Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology. 査読有り

Tsujikawa K, Hamanaka K, Riku Y, Hattori Y, Hara N, Iguchi Y, Ishigaki S, Hashizume A, Miyatake S, Mitsuhashi S, Miyazaki Y, Kataoka M, Jiayi L, Yasui K, Kuru S, Koike H, Kobayashi K, Sahara N, Ozaki N, Yoshida M, Kakita A, Saito Y, Iwasaki Y, Miyashita A, Iwatsubo T, Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI), Ikeuchi T, Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC) Consortium, Miyata T, Sobue G, Matsumoto N, Sahashi K, Katsuno M

Science advances 8 巻 ( 21 ) 頁： eabm5029 2022年5月

記述言語：英語出版者・発行元：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

Scopus

PubMed

Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex. 査読有り

Hattori Y, Itoh H, Tsugawa Y, Nishida Y, Kurata K, Uemura A, Miyata T

Journal of Neuroscience 42 巻 ( 3 ) 頁： 362 - 376 2022年1月

担当区分：最終著者記述言語：英語出版者・発行元：The Journal of neuroscience : the official journal of the Society for Neuroscience

Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through in vivo pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)β (clone APB5), we found that microglial density was markedly decreased compared with that in control antibody-treated brains because of their low proliferative capacity. Moreover, in vitro coculture of isolated CD11b+ microglia and NG2+PDGFRα- cells, which are mostly composed of pericytes, from parenchymal cells indicated that pericytes promote microglial proliferation via the production of soluble factors. Furthermore, pericyte depletion by APB5 treatment resulted in a failure of microglia to promote the differentiation of neural stem cells into intermediate progenitors. Taken together, our findings suggest that pericytes facilitate microglial homeostasis in the developing brains, thereby indirectly supporting microglial effects on neural progenitors.SIGNIFICANCE STATEMENT This study highlights the novel effect of pericytes on microglia in the developing mouse brain. Through multiple analyses using an in vivo pericyte depletion mouse model and an in vitro coculture study of isolated pericytes and microglia from parenchymal cells, we demonstrated that pericytes contribute to microglial proliferation and support microglia in efficiently promoting the differentiation of neural stem cells into intermediate progenitors. Our present data provide evidence that pericytes function not only in the maintenance of cerebral microcirculation and blood brain barrier (BBB) integrity but also in microglial homeostasis in the developing cerebral walls. These findings will expand our knowledge and help elucidate the mechanism of brain development both in healthy and disease conditions.

DOI： 10.1523/JNEUROSCI.1201-21.2021

Scopus

PubMed

Developmentally interdependent stretcher-compressor relationship between the embryonic brain and the surrounding scalp in the preosteogenic head. 査読有り

Tsujikawa K, Saito K, Nagasaka A, Miyata T

Developmental Dynamics 2022年1月

担当区分：最終著者,　責任著者記述言語：英語出版者・発行元：Developmental Dynamics

Background: How developing brains mechanically interact with the surrounding embryonic scalp layers (ie, epidermal and mesenchymal) in the preosteogenic head remains unknown. Between embryonic day (E) 11 and E13 in mice, before ossification starts in the skull vault, the angle between the pons and the medulla decreases, raising the possibility that when the elastic scalp is directly pushed outward by the growing brain and thus stretched, it recoils inward in response, thereby confining and folding the brain. Results: Stress-release tests showed that the E11-13 scalp recoiled and that the in vivo prestretch prerequisite for this recoil was physically dependent on the brain (pressurization at 77-93 Pa) and on actomyosin and elastin within the scalp. In scalp-removed heads, brainstem folding was reduced, and the spreading of ink from the lateral ventricle to the spinal cord that occurred in scalp-intact embryos (with >5 μL injection) was lost, suggesting roles of the embryonic scalp in brain morphogenesis and cerebrospinal fluid homeostasis. Under nonstretched conditions, scalp cell proliferation declined, while the restretching of the shrunken scalp rescued scalp cell proliferation. Conclusions: In the embryonic mouse head before ossification, a stretcher-compressor relationship elastically develops between the brain and the scalp, underlying their mechanically interdependent development.

DOI： 10.1002/dvdy.451

Scopus

PubMed

Comparison of the Mechanical Properties Between the Convex and Concave Inner/Apical Surfaces of the Developing Cerebrum 査読有り

Frontiers in Cell and Developmental Biology 9 巻 2021年7月

A mouse model of microglia-specific ablation in the embryonic central nervous system. 査読有り

Li C, Konishi H, Nishiwaki K, Sato K, Miyata T, Kiyama H

Neuroscience Research 2021年6月

記述言語：英語出版者・発行元：Neuroscience Research

Microglia, which migrate into the central nervous system (CNS) during the early embryonic stages, are considered to play various roles in CNS development. However, their embryonic roles are largely unknown, partly due to the lack of an effective microglial ablation system in the embryo. Here, we show a microglial ablation model by injecting diphtheria toxin (DT) into the amniotic fluid of Siglechdtr mice, in which the gene encoding DT receptor is knocked into the microglia-specific gene locus Siglech. We revealed that embryonic microglia were depleted for several days throughout the CNS, including some regions where microglia transiently accumulated, at any embryonic time point from embryonic day 10.5, when microglia colonize the CNS. This ablation system was specific for microglia because CNS-associated macrophages, which are a distinct population from microglia that reside in the CNS interfaces such as meninges, were unaffected. Therefore, this microglial ablation system is highly effective for studying the embryonic functions of microglia.

DOI： 10.1016/j.neures.2021.06.002

Scopus

PubMed

大脳皮質の発生における力学招待有り

宮田卓樹

38 巻頁： 1510 - 1512 2020年12月

Two-photon microscopic observation of cell-production dynamics in the developing mammalian neocortex in utero. 招待有り査読有り

Kawasoe R, Shinoda T, Hattori Y, Nakagawa M, Pham TQ, Tanaka Y, Sagou K, Saito K, Katsuki S, Kotani T, Sano A, Fujimori T, Miyata T.

Development, Growth & Differentiation 62 巻頁： 118 - 128 2020年1月

Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis 招待有り査読有り国際共著

Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, Ando K, Weng L, Ishihara S, Ponik SM, Conklin MH, Haga H, Nagasaka A, Miyata T, Matsuyama M, Kobayashi T, Fujii T, Yamada S, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Takahashi M, and Enomoto A

Cancer Research 79 巻頁： 5367 - 5381 2019年10月

Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction

Hara Akitoshi, Kobayashi Hiroki, Asai Naoya, Saito Shigeyoshi, Higuchi Takahiro, Kato Katsuhiro, Okumura Takahiro, Bando Yasuko K., Takefuji Mikito, Mizutani Yasuyuki, Miyai Yuki, Saito Shoji, Maruyama Shoichi, Maeda Keiko, Ouchi Noriyuki, Nagasaka Arata, Miyata Takaki, Mii Shinji, Kioka Noriyuki, Worthley Daniel L., Murohara Toyoaki, Takahashi Masahide, Enomoto Atsushi

CIRCULATION RESEARCH 125 巻 ( 4 ) 頁： 414-430 2019年8月

Lzts1 controls both neuronal delamination and outer radial glial-like cell generation during mammalian cerebral development 査読有り

Kawaue T., Shitamukai A., Nagasaka A., Tsunekawa Y., Shinoda T., Saito K., Terada R., Bilgic M., Miyata T., Matsuzaki F., Kawaguchi A.

NATURE COMMUNICATIONS 10 巻 2019年6月

[Production Logistics and Crowd Dynamics in the Developing Cerebral Cortex].

Miyata T

Brain and nerve = Shinkei kenkyu no shinpo 71 巻 ( 4 ) 頁： 415-421 2019年4月

大脳皮質形成の生産物流とクラウドダイナミクス招待有り査読有り

宮田卓樹

71 巻頁： 415 - 421 2019年4月

生体イメージングと眼病理統合的アプローチによる糖尿病網膜症研究の新展開査読有り

植村明嘉, 小椋俊太郎, 小椋俊太郎, 倉田薫里, 小峯祐美, 大矢恵, 井上奈緒美, 井上奈緒美, 小椋祐一郎, 高瀬弘嗣, 宮田卓樹, 福嶋葉子, 楠原仙太郎, 平島正則, 池田わたる, 南敬, 渋谷正史, 吉田富, MANN Fanny, 酒井秀人, 奈良裕美, YANCOPOULOS George D, WIEGAND Stanley J, KIM Pilhan, KOH Gou Young, 西川伸一

日本眼科学会雑誌 123 巻 ( 3 ) 頁： 312 - 336 2019年

記述言語：日本語出版者・発行元：(公財)日本眼科学会

近年の眼底イメージングの進歩により、糖尿病網膜症における細小血管障害の診断技術は飛躍的に向上した。しかし、その背景にある、細胞・分子レベルの異常については、未だ不明な点が多い。そこで我々は、糖尿病網膜症と同様の血管病変をマウスで再現し、生体イメージングを含むさまざまな解析手法を統合することにより、病態解明と新規創薬開発を目指した基礎研究に取り組んできた。1.生体マウス網膜イメージング糖尿病網膜症の発症・進展過程では、さまざまな細胞がダイナミックに形態を変化させ、網膜組織内を移動すると考えられる。こうした細胞動態を捉えるため、我々は生体マウス網膜におけるリアルタイム・イメージング技術の開発を進めてきた。我々はまず、麻酔下のマウスで進行する白内障を防止し、6時間以上にわたって眼底透見性を維持するコンタクトレンズを開発した。次にこのコンタクトレンズを、共焦点蛍光顕微鏡や二光子励起蛍光顕微鏡と組み合わせることにより、生理的および病的状況における網膜ミクログリアやマクロファージ、さらに網膜循環内の白血球や血流の動態を観察することに成功した。こうした技術を応用することにより、網膜の恒常性維持や疾患における分子メージングも可能になると期待される。2.ペリサイト消失よる網膜血管異常 1960年代に報告されたヒト眼の病理組織解析をもとに、糖尿病網膜症では毛細血管壁のペリサイトが消失することによって、多様な血管障害が発症すると考えられてきた。しかし、高血糖モデル動物ではヒト網膜症と同様の病理変化を再現できないため、ペリサイト消失の病態生理学的意義については十分に解明されていない。こうした問題を克服するため、我々はplatelet-derived growth factor receptorβに対するモノクローナル抗体を新生仔マウスに投与することにより、高血糖を介さずに網膜血管壁のペリサイト集積を阻害する実験モデルを確立した。ペリサイトを消失した網膜では、血管壁が拡張・蛇行するとともに多数の毛細血管瘤が形成され、血管透過性の亢進に伴って浮腫・出血が急速に進行した。さらにペリサイト消失網膜に浸潤したマクロファージと内皮細胞が、vascular endothelial growth factor A、placental growth factor、angiopoietin-2を介した連鎖回路を形成することにより、炎症が遷延し、血管壁バリア機能が不可逆的に破綻することが明らかとなった。これらの結果から、糖尿病網膜症にみられる一連の病理変化が、ペリサイト消失を契機として連続的に進行しうると考えられた。3.虚血網膜における血管再生増殖糖尿病網膜症では、新生血管が硝子体腔に向かって伸長するため、網膜虚血が一向に改善されない。こうした状況において新生血管を網膜内に誘導し、機能的血管網を再生することができれば、網膜虚血に対する根治療法の開発につながると期待される。そこで我々は、新生仔マウスにおいて新生血管が網膜内に整然と伸長する過程を解析することにより、ニューロン由来のsemaphorin 3E(Sema3E)が内皮細胞のPlexinD1受容体に結合して低分子量G蛋白質RhoJを活性化し、誤った方向に伸長する血管新生を退縮させることを明らかにした。我々はさらに、虚血網膜症モデルマウスの眼内にSema3E蛋白質を投与して、硝子体腔に逸脱する新生血管のPlexinD1を活性化することにより、網膜血管再生に影響を及ぼすことなく、異常血管新生を選択的に阻害することに成功した。これらの結果から、Sema3E-PlexinD1-RhoJシグナルの活性化による、網膜血管再生療法の可能性が示唆された。(著者抄録)

J-GLOBAL

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01049&link_issn=&doc_id=20190313340005&doc_link_id=%2Fdz1nigan%2F2019%2F012303%2F005%2F0312-0336%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz1nigan%2F2019%2F012303%2F005%2F0312-0336%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

神経幹細胞による「他力」活用：集団的核移動の効率と細胞産生の安全招待有り査読有り

篠田友靖，川上巧，宮田卓樹

90 巻 ( 6 ) 頁： 820 - 824 2018年12月

Embryonic Neocortical Microglia Express Toll-Like Receptor 9 and Respond to Plasmid DNA Injected into the Ventricle: Technical Considerations Regarding Microglial Distribution in Electroporated Brain Walls.

Hattori Y, Miyata T

eNeuro 5 巻 ( 6 ) 2018年11月

Microglia extensively survey the developing cortex via the CXCL12/CXCR4 system to help neural progenitors to acquire differentiated properties.

Hattori Y, Miyata T

Genes to cells : devoted to molecular & cellular mechanisms 2018年8月

Role of extrinsic mechanical force in the development of the RA-I tactile mechanoreceptor

Trung Quang Pham, Kawaue Takumi, Hoshi Takayuki, Tanaka Yoshihiro, Miyata Tataki, Sano Akihito

SCIENTIFIC REPORTS 8 巻 2018年7月

Synaptic transmission from subplate neurons controls radial migration of neocortical neurons

Ohtaka-Maruyama Chiaki, Okamoto Mayumi, Endo Kentaro, Oshima Minori, Kaneko Noe, Yura Kei, Okado Haruo, Miyata Takaki, Maeda Nobuaki

SCIENCE 360 巻 ( 6386 ) 頁： 313-316 2018年4月

Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury 査読有り

Jinnou H, Sawada M, Kawase K, Kaneko N, Herranz-Pérez V, Miyamoto T, Kawaue T, Miyata T, Tabata Y, Akaike T, García-Verdugo JM, Ajioka I, Saitoh S, Sawamoto K.

Cell Stem Cell. 22 巻 ( 1 ) 頁： 128–137.e9 2018年1月

Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon. 査読有り

Saito K, Kawasoe R, Sasaki H, Kawaguchi A, Miyata T.

Neurochemical Research 43 巻 ( 1 ) 頁： 171–180 2018年1月

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