担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Communications  

Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration.

DOI： 10.1038/s41467-024-45825-8

Scopus

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biomaterials  

The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)3-(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy.

DOI： 10.1016/j.biomaterials.2023.122003

Scopus

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Current Opinion in Neurobiology  

Postnatal neuronal migration modulates neuronal circuit formation and function throughout life and is conserved among species. Pathological conditions activate the generation of neuroblasts in the ventricular-subventricular zone (V-SVZ) and promote their migration towards a lesion. However, the neuroblasts generally terminate their migration before reaching the lesion site unless their intrinsic capacity is modified or the environment is improved. It is important to understand which factors impede neuronal migration for functional recovery of the brain. We highlight similarities and differences in the mechanisms of neuroblast migration under physiological and pathological conditions to provide novel insights into endogenous neuronal regeneration.

DOI： 10.1016/j.conb.2020.06.001

Scopus

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COMPANY OF BIOLOGISTS LTD  

Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migration. Our studies thus identify LRP1 as a novel player in angiogenesis and in the recruitment and maintenance of mural cells. Moreover, they reveal an unexpected link between lipoprotein receptor and sphingolipid signaling that, in addition to angiogenesis during embryonic development, is of potential importance for other targets of these pathways, such as tumor angiogenesis and inflammatory processes.

DOI： 10.1242/dev.109124

Web of Science

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The lipoprotein receptor LRP1 is essential in neurons of the central nervous system, as was revealed by the analysis of conditional Lrp1-deficient mouse models. The molecular basis of its neuronal functions, however, is still incompletely understood. Here we show by immunocytochemistry, electron microscopy, and postsynaptic density preparation that LRP1 is located postsynaptically. Basal and NMDA-induced phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) as well as NMDA target gene transcription are reduced in LRP1-deficient neurons. In control neurons, NMDA promotes -secretase-dependent release of the LRP1 intracellular domain (LRP1-ICD). However, pull-down and chromatin immunoprecipitation (ChIP) assays showed no direct interaction between the LRP1-ICD and either CREB or target gene promoters. On the other hand, NMDA-induced degradation of the postsynaptic scaffold protein PSD-95 was impaired in the absence of LRP1, whereas its ubiquitination was increased, indicating that LRP1 influences the composition of postsynaptic protein complexes. Accordingly, NMDA-induced internalization of the AMPA receptor subunit GluA1 was impaired in LRP1-deficient neurons. These results show a role of LRP1 in the regulation and turnover of synaptic proteins, which may contribute to the reduced dendritic branching and to the neurological phenotype observed in the absence of LRP1.

DOI： 10.1074/jbc.M112.444364

Web of Science

PubMed

担当区分：筆頭著者   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

担当区分：筆頭著者  

J-GLOBAL

担当区分：筆頭著者  

J-GLOBAL

開催年月日： 2024年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催年月日： 2024年6月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2024年3月

会議種別：口頭発表（一般）  

開催年月日： 2023年7月

会議種別：口頭発表（招待・特別）  

開催年月日： 2018年5月

会議種別：ポスター発表  

出願人：公立大学法人名古屋市立大学

出願番号：特願PCT/JP2023/8130  出願日：2023年3月

出願人：公立大学法人名古屋市立大学

出願番号：特願2022-34331  出願日：2022年3月

出願人：公立大学法人名古屋市立大学

出願番号：特願PCT/JP2020/47678  出願日：2020年12月

種別：学会・研究会等 

種別：大会・シンポジウム等