上顎の形態発生におけるWnt signaling pathwayの役割

Cleft lip with or without cleft palate (CLP) usually results from a failure of the medial nasal prominences to fuse with the lateral and maxillary prominences. This failure inhibits facial morphogenesis regulated by several major morphogenetic signaling pathways. We hypothesized that CLP results from the failure of the Wnt signaling pathway. To examine whether Wnt signaling can influences upper jaw development, we applied beads soaked with Dickkopf-1 (Dkk-1), Alsterpaullone (AL) or Wnt3a to the right side of the maxillary prominence of the chick embryo. The embryo showed a defect of the maxilla on the treated side, and skeletal staining revealed hypoplasia of the premaxilla and palatine bone as a result of Dkk-1-soaked bead implantation. 5-bromo-2'-deoxyuridine (BrdU)-positive cell numbers in the treated maxillary prominence were significantly lower at both 24 and 48 hr after implantation. Down-regulation of the expression of Bmp4, Tbx22, Sox9, and Barx1 was confirmed in the maxillary prominence treated with Dkk-1, which indicated that the deformity of the maxillary bone was controlled by gene targets of the Wnt signaling pathway. Expression of N-cadherin was seen immunohistochemically in the maxillary prominences of embryos at 6 hr and increased at 24 hr after AL treatment. Wnt signaling enhanced by AL or Wnt3a up-regulated the expression levels of Msx1, Bmp4, Tbx22, Sox9, and Barx1. Our data suggest that the Wnt signaling pathway regulates maxillary morphogenesis and growth through Bmp4, Tbx22, Sox9, and Barx1. Wnt signaling might regulate N-cadherin expression via Msx1, resulting in cell aggregation for osteochondrogenesis.博士（医学）・乙第1430号・令和元年6月26日© 2019 The Japan Society of Histochemistry and CytochemistryCopyright: © 2019 The author. This is an open access article distributed under the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, istribution, and reproduction in any medium, provided the original work is properly cited.J-STAGEへのリンク : http://dx.doi.org/10.1267/ahc.1803

Spared nerve injury後のマウス後根神経節におけるNGFとBDNFの発現

Neuropathic pain is initiated by a primary lesion in the peripheral nervous system and spoils quality of life. Neurotrophins play important roles in the development and transmission of neuropathic pain. There are conflicting reports that the dorsal root ganglion (DRG) in an injured nerve contribute to neuropathic pain, whereas several studies have highlighted the important contribution of the DRG in a non-injured nerve. Clarifying the role of neurotrophins in neuropathic pain is problematic because we cannot distinguish injured and intact neurons in most peripheral nerve injury models. In the present study, to elicit neuropathic pain, we used the spared nerve injury (SNI) model, in which injured DRG neurons are distinguishable from intact ones, and mechanical allodynia develops in the intact sural nerve skin territory. We examined nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRGs of SNI model mice. NGF and BDNF levels increased in the injured L3 DRG, while NGF decreased in the intact L5 DRG. These data offer a new point of view on the role of these neurotrophins in neuropathic pain induced by peripheral nerve injury.博士（医学）・甲第698号・平成31年3月15日© 2018 Elsevier B.V. All rights reserved

精神疾患におけるマイクログリア由来ニューレグリン発現

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.博士（医学）・乙第1404号・平成29年6月28日Copyright © 2017 Elsevier Inc. All rights reserved

脱髄および再髄鞘化におけるニューロシンの発現意義およびその作用機序

雑誌掲載

平成22・23年度「独創性のある生命科学研究」個別研究課題 2）ミクログリアを介した髄鞘再生機序の解明

雑誌掲載

Cuprizone誘発性脱髄モデル動物における脱髄と再ミエリン化

脱髄疾患は神経軸索を取り囲むミエリンが破壊する疾患であり、中枢神経系では多発性硬化症(MS)がその代表例である。MSの発症には遺伝および環境要因の両者が関わっているが、詳細な発症機序はいまだ不明である。MSの病因解明や治療法の開発を進めるうえで、その動物実験モデルの研究は極めて重要であるが、それぞれのモデルには一長一短があり、どのモデルが最適であるとはいえない。MSの研究を進めるためにはヒトと動物との間にみられる類似点と相違点を明確に把握したうえで利用することが望ましい。本稿ではtoxic demyelination modelの一つであるcuprizone誘発性脱髄モデルにおける脱髄機序やグリア細胞の役割について概説し、このモデルを用いたMSの病因や再ミエリン化機序の解明に向けた取り組みや最近の知見を紹介す

平成24・25年度「独創性のある生命科学研究」個別研究課題 ６）ミクログリアの活性化を調節する内在性制御因子の同定

雑誌掲載

平成23.24年度「独創性のある生命科学研究」個別研究課題 4）ミクログリア由来CNTFを介したミエリン再生機序の解明

雑誌掲載