103 results on '"Arikawa-Hirasawa E"'
Search Results
2. Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches
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Kerever, A., Nagahara, F., Keino-Masu, K., Masu, M., Kuppevelt, T.H. van, Vivès, R.R., Arikawa-Hirasawa, E., Kerever, A., Nagahara, F., Keino-Masu, K., Masu, M., Kuppevelt, T.H. van, Vivès, R.R., and Arikawa-Hirasawa, E.
- Abstract
Item does not contain fulltext, Fractones, specialized extracellular matrix structures found in the subventricular zone (SVZ) neurogenic niche, can capture growth factors, such as basic fibroblast growth factor, from the extracellular milieu through a heparin-binding mechanism for neural stem cell (NSC) presentation, which promotes neurogenesis. During aging, a decline in neurogenesis correlates with a change in the composition of heparan sulfate (HS) within fractones. In this study, we used antibodies that recognize specific short oligosaccharides with varying sulfation to evaluate the HS composition in fractones in young and aged brains. To further understand the conditions that regulate 6-O sulfation levels and its impact on neurogenesis, we used endosulfatase Sulf1 and Sulf2 double knockout (DKO) mice. Fractones in the SVZ of Sulf1/2 DKO mice showed immunoreactivity for the HS epitope, suggesting higher 6-O sulfation. While neurogenesis declined in the aged SVZ of both wild-type and Sulf1/2 DKO mice, we observed a larger number of neuroblasts in the young and aged SVZ of Sulf1/2 DKO mice. Together, these results show that the removal of 6-O-sulfation in fractones HS by endosulfatases inhibits neurogenesis in the SVZ. Our findings advance the current understanding regarding the extracellular environment that is best suited for NSCs to thrive, which is critical for the design of future stem cell therapies.
- Published
- 2021
3. Fractone-heparan sulphates mediate FGF-2 stimulation of cell proliferation in the adult subventricular zone
- Author
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Douet, V., Kerever, A., Arikawa-Hirasawa, E., and Mercier, F.
- Published
- 2013
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4. Role of synovial perlecan in osteophyte formation in early stage knee osteoarthritis
- Author
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Arita, H., primary, Kaneko, H., additional, Kinoshita, M., additional, Hada, S., additional, Sadatsuki, R., additional, Futami, I., additional, Negishi, Y., additional, Momoeda, M., additional, Liu, L., additional, Aoki, T., additional, Arikawa-Hirasawa, E., additional, Kaneko, K., additional, and Ishijima, M., additional
- Published
- 2019
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5. Perlecan, a heparan surfate proteoglycan, regulates metabolic dynamics
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Yamashita, Y., primary, Nakada, S., additional, Yoshihara, T., additional, Hattori, N., additional, and Arikawa-Hirasawa, E., additional
- Published
- 2017
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6. The role of perlecan in nnos mediated mechanotransduction in skeletal muscle
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Arikawa-Hirasawa, E., primary, Nakada, S., additional, Yamashita, Y., additional, and Hattori, N., additional
- Published
- 2017
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7. Mutations in the perlecan gene of Schwartz-Jampel syndrome: critical role of perlecan in neuromuscular junction functions
- Author
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Arikawa-Hirasawa, E., Le, A.H., Nishino, I., Nonaka, I., Ho, N.C., Francomano, C.A., Govindra, P., Hassell, J.R., Devaney, J.M., Spranger, J., Stevenson, R.E., Iannaccone, S., Dalakas, M.C., and Yamada, Y.
- Subjects
Human genetics -- Research ,Genetic disorders -- Research ,Proteoglycans -- Genetic aspects ,Musculoskeletal diseases -- Genetic aspects ,Biological sciences - Published
- 2001
8. The effect of laminin-1 on enteric neural crest-derived cell migration in the Hirschsprung's disease mouse model.
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Nakazawa-Tanaka, Nana, Fujiwara, N., Miyahara, K., Nakada, S., Arikawa-Hirasawa, E., Akazawa, C., Urao, M., and Yamataka, A.
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LAMININS ,NEURAL crest ,CELL migration ,HIRSCHSPRUNG'S disease ,ANIMAL models in research ,CELL differentiation ,ANIMAL experimentation ,AUTONOMIC nervous system ,BIOLOGICAL models ,CELL culture ,CELL motility ,DNA ,GENES ,IMMUNOHISTOCHEMISTRY ,MEMBRANE proteins ,MICE ,POLYMERASE chain reaction ,EMBRYOS ,PHYSIOLOGY - Abstract
Background/aim: Laminin-1 regulates neurite outgrowth in various neuronal cells. We have previously demonstrated that laminin-1 promotes enteric neural crest-derived cell (ENCC) migration by using Sox10-VENUS transgenic mice, in which ENCCs are labeled with a green fluorescent protein, Venus. Mice lacking the endothelin-B receptor gene, Ednrb -/- mice, are widely used as a model for Hirschsprung's disease (HD). The aim of this study was to investigate the effects of laminin-1on ENCC migration in Sox10-VENUS+/Ednrb -/- mice, a newly created HD mice model.Methods: Fetal guts were dissected on embryonic day 12.5 (E12.5). Specimens were incubated either with, or without laminin-1 for 24 h and images were taken under a stereoscopic microscope. The length from the stomach to the wavefront of ENCC migration (L-E) and the total length of the gut (L-G) were measured. Changes in the ratio of L-E to L-G (L-E/L-G) after 24 h were calculated.Results: On E12.5, the wavefront of ENCC migration in the HD gut samples was located in the midgut, whereas the wavefront of ENCC in Sox10-VENUS+/Ednrb +/+ (WT) samples had reached the hindgut. After 24 h, L-E/L-G had increased by 1.49%, from 34.97 to 36.46%, in HD gut and had increased by 1.07%, from 48.08 to 49.15%, in HD with laminin-1, suggesting there was no positive effect of laminin-1 administration on ENCC migration in HD.Conclusions: Our results suggest that laminin-1 does not have a positive effect on ENCC migration in HD mice on E12.5, in contrast to the phenomenon seen in normal mice gut specimens, where laminin-1 promotes ENCC migration during the same period. This suggests that there is an impairment in the interaction between ENCC and extracellular environmental factors, which are required for normal development of the enteric nervous system, resulting in an aganglionic colon in HD. [ABSTRACT FROM AUTHOR]- Published
- 2018
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9. Role of perlecan in chondrogenic, osteogenic and adipogenic differentiation of synovial mesenchymal calls
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Sadatsuki, R., primary, Kaneko, H., additional, Futami, I., additional, Hada, S., additional, Culley, K.L., additional, Otero, M., additional, Dragomir, C., additional, Kinoshita, M., additional, Goldring, M.B., additional, Yamada, Y., additional, Arikawa-Hirasawa, E., additional, Kaneko, K., additional, and Ishijima, M., additional
- Published
- 2014
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10. Teneurin-4 Is a Novel Regulator of Oligodendrocyte Differentiation and Myelination of Small-Diameter Axons in the CNS
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Suzuki, N., primary, Fukushi, M., additional, Kosaki, K., additional, Doyle, A. D., additional, de Vega, S., additional, Yoshizaki, K., additional, Akazawa, C., additional, Arikawa-Hirasawa, E., additional, and Yamada, Y., additional
- Published
- 2012
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11. Pigment epithelium-derived factor up-regulation induced by memantine, an N-methyl-d-aspartate receptor antagonist, is involved in increased proliferation of hippocampal progenitor cells
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Namba, T., primary, Yabe, T., additional, Gonda, Y., additional, Ichikawa, N., additional, Sanagi, T., additional, Arikawa-Hirasawa, E., additional, Mochizuki, H., additional, Kohsaka, S., additional, and Uchino, S., additional
- Published
- 2010
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12. 015 COMPARISON OF THE EXPRESSION PROFILES OF SYNOVIAL TISSUE INFLAMMATION BETWEEN END-STAGE AND PROGRESSIVE KNEE OSTEOARTHRITIS
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Liang, N., primary, Kaneko, H., additional, Ishijima, M., additional, Kubota, M., additional, Futami, I., additional, Zu, L., additional, Kawasaki, T., additional, Takazawa, Y., additional, Ikeda, H., additional, Kurihara, H., additional, Arikawa-Hirasawa, E., additional, and Kurosawa, H., additional
- Published
- 2009
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13. A severe muscular dystrophy patient with an internally deleted very short (110 kD) Dystrophin: Presence of the binding site for dystrophin-associated glycoprotein (DAG) may not be enough for physiological function of dystrophin
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Arikawa-Hirasawa, E., primary, Koga, R., additional, Tsukahara, T., additional, Nonaka, I., additional, Mitsudome, A., additional, Goto, K., additional, Beggs, A.H., additional, and Arahata, K., additional
- Published
- 1995
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14. Differential expression of laminin a chains during proliferative and differentiation stages in a model for skin morphogenesis
- Author
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Fleischmajer, R., Kuroda, K., Utani, A., II, E. Douglas MacDonald, Perlish, J. S., Arikawa-Hirasawa, E., Sekiguchi, K., Sanzen, N., Timpl, R., and Yamada, Y.
- Published
- 2000
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15. Abnormal localization of laminin subunits in muscular dystrophies
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Hayashi, Y. K., Engvail, E., Arikawa-Hirasawa, E., and Goto, K.
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- 1993
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16. Dyssegmental dysplasia Rolland-Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients.
- Author
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Farshadyeganeh P, Yamada T, Ohashi H, Nishimura G, Fujita H, Oishi Y, Nunode M, Ishikawa S, Murotsuki J, Yamashita Y, Ikegawa S, Ogi T, Arikawa-Hirasawa E, and Ohno K
- Subjects
- Female, Humans, Male, Alleles, Bone Diseases, Developmental genetics, Bone Diseases, Developmental pathology, Founder Effect, Mutation, Fetal Diseases, Haplotypes, Heparan Sulfate Proteoglycans genetics, Osteochondrodysplasias genetics, Osteochondrodysplasias pathology
- Abstract
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2., (© 2024. The Author(s).)
- Published
- 2024
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17. Beyond 2D: A scalable and highly sensitive method for a comprehensive 3D analysis of kidney biopsy tissue.
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Yamada H, Makino SI, Okunaga I, Miyake T, Yamamoto-Nonaka K, Oliva Trejo JA, Tominaga T, Empitu MA, Kadariswantiningsih IN, Kerever A, Komiya A, Ichikawa T, Arikawa-Hirasawa E, Yanagita M, and Asanuma K
- Abstract
The spatial organization of various cell populations is critical for the major physiological and pathological processes in the kidneys. Most evaluation of these processes typically comes from a conventional 2D tissue cross-section, visualizing a limited amount of cell organization. Therefore, the 2D analysis of kidney biopsy introduces selection bias. The 2D analysis potentially omits key pathological findings outside a 1- to 10-μm thin-sectioned area and lacks information on tissue organization, especially in a particular irregular structure such as crescentic glomeruli. In this study, we introduce an easy-to-use and scalable method for obtaining high-quality images of molecules of interest in a large tissue volume, enabling a comprehensive evaluation of the 3D organization and cellular composition of kidney tissue, especially the glomerular structure. We show that CUBIC and ScaleS clearing protocols could allow a 3D analysis of the kidney tissues in human and animal models of kidney disease. We also demonstrate that the paraffin-embedded human biopsy specimens previously examined via 2D evaluation could be applicable to 3D analysis, showing a potential utilization of this method in kidney biopsy tissue collected in the past. In summary, the 3D analysis of kidney biopsy provides a more comprehensive analysis and a minimized selection bias than 2D tissue analysis. Additionally, this method enables a quantitative evaluation of particular kidney structures and their surrounding tissues, with the potential utilization from basic science investigation to applied diagnostics in nephrology., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)
- Published
- 2024
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18. Oligodendrocyte Cell Line OLP6 Successfully Differentiates on Decellularized Brain Tissue.
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Kato K, Nishimura H, Suzuki Y, Tanaka T, Abe R, Kerever A, and Arikawa-Hirasawa E
- Abstract
Objectives: The mechanisms of mental and neurological diseases have been proposed to be related not only to disorders of the neurons but also to the environment surrounding neurons, such as glial cells and the extracellular matrix (ECM). The chondroitin sulfate (CS) chain, which comprises CS proteoglycans (CSPGs), is one of the major sulfated glycosaminoglycans in the brain. CSPGs play an important role in the development, aging, and pathological conditions of the central nervous system. In particular, CSPGs play critical roles in oligodendrocyte differentiation and cell activity. Conventional two-dimensional culture in a glass chamber hardly replicates the complexity of the ECM structure or mimics in vivo conditions. Therefore, to solve this issue, this study aimed to use a culture system with decellularized tissue as a scaffold of organized ECM, thereby enabling the observation of cell differentiation and interactions between cells and the surrounding ECM., Materials and Methods: We investigated the differentiation potential of the OLP6 cell line using decellularized brain tissue as the substrate., Results: We observed that OLP6 differentiated faster on decellularized brain tissues than on conventional 2D-coated surfaces. The relative mRNA expression levels of CNP , PNP , and MBP as well as CSPGs were increased under 3D culture conditions., Conclusions: Our study provides the first evidence of the advantages of cell culture on decellularized tissues for the investigation of oligodendrocyte differentiation and cell/ECM interactions., Competing Interests: The authors declare that there are no conflicts of interest. All experiments were conducted in compliance with the ARRIVE guidelines., (2023 ©The Juntendo Medical Society.)
- Published
- 2023
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19. Evaluation of a Medical Interview-Assistance System Using Artificial Intelligence for Resident Physicians Interviewing Simulated Patients: A Crossover, Randomized, Controlled Trial.
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Kanazawa A, Fujibayashi K, Watanabe Y, Kushiro S, Yanagisawa N, Fukataki Y, Kitamura S, Hayashi W, Nagao M, Nishizaki Y, Inomata T, Arikawa-Hirasawa E, and Naito T
- Subjects
- Humans, Bayes Theorem, Japan, Artificial Intelligence, Physicians
- Abstract
Medical interviews are expected to undergo a major transformation through the use of artificial intelligence. However, artificial intelligence-based systems that support medical interviews are not yet widespread in Japan, and their usefulness is unclear. A randomized, controlled trial to determine the usefulness of a commercial medical interview support system using a question flow chart-type application based on a Bayesian model was conducted. Ten resident physicians were allocated to two groups with or without information from an artificial intelligence-based support system. The rate of correct diagnoses, amount of time to complete the interviews, and number of questions they asked were compared between the two groups. Two trials were conducted on different dates, with a total of 20 resident physicians participating. Data for 192 differential diagnoses were obtained. There was a significant difference in the rate of correct diagnosis between the two groups for two cases and for overall cases (0.561 vs. 0.393; p = 0.02). There was a significant difference in the time required between the two groups for overall cases (370 s (352-387) vs. 390 s (373-406), p = 0.04). Artificial intelligence-assisted medical interviews helped resident physicians make more accurate diagnoses and reduced consultation time. The widespread use of artificial intelligence systems in clinical settings could contribute to improving the quality of medical care.
- Published
- 2023
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20. Evaluation of Human-Induced Pluripotent Stem Cells Derived from a Patient with Schwartz-Jampel Syndrome Revealed Distinct Hyperexcitability in the Skeletal Muscles.
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Yamashita Y, Nakada S, Nakamura K, Sakurai H, Ohno K, Goto T, Mabuchi Y, Akazawa C, Hattori N, and Arikawa-Hirasawa E
- Abstract
Schwartz-Jampel syndrome (SJS) is an autosomal recessive disorder caused by loss-of-function mutations in heparan sulfate proteoglycan 2 ( HSPG2 ), which encodes the core basement membrane protein perlecan. Myotonia is a major criterion for the diagnosis of SJS; however, its evaluation is based solely on physical examination and can be challenging in neonates and young children. Furthermore, the pathomechanism underlying SJS-related myotonia is not fully understood, and effective treatments for SJS are limited. Here, we established a cellular model of SJS using patient-derived human-induced pluripotent stem cells. This model exhibited hyper-responsiveness to acetylcholine as a result of abnormalities in the perlecan molecule, which were confirmed via comparison of their calcium imaging with calcium imaging of satellite cells derived from Hspg2
-/- -Tg mice, which exhibit myotonic symptoms similar to SJS symptoms. Therefore, our results confirm the utility of creating cellular models for investigating SJS and their application in evaluating myotonia in clinical cases, while also providing a useful tool for the future screening of SJS therapies.- Published
- 2023
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21. α-1,6-Fucosyltransferase Is Essential for Myogenesis in Zebrafish.
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Hayashiji N, Kawahara G, Xu X, Fukuda T, Kerever A, Gu J, Hayashi YK, and Arikawa-Hirasawa E
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- Humans, Animals, Mice, Muscle Fibers, Skeletal metabolism, Glycosylation, Muscle Development genetics, Zebrafish genetics, Fucosyltransferases genetics, Fucosyltransferases metabolism
- Abstract
Glycosylation is an important mechanism regulating various biological processes, including intercellular signaling and adhesion. α-1,6-fucosyltransferase (Fut8) belongs to a family of enzymes that determine the terminal structure of glycans. Fut8 is widely conserved from Caenorhabditis elegans to humans, and its mutants have been reported in humans, mice, and zebrafish. Although mutants show various symptoms, such as spinal deformity and growth retardation, its effects on skeletal muscles are unknown. We aimed to elucidate the function of Fut8 in skeletal muscle using zebrafish and C2C12 cells for evaluation. We observed that most fut8a morphants died at 2 days post-fertilization (dpf) or in earlier developmental stages even at low concentrations of morpholino oligonucleotides (MOs). Mutant juveniles also had small body sizes, and abnormal myocepta and sarcomere structures, suggesting that Fut8a plays important roles in myogenesis. Moreover, treatment of C2C12 cells with 2-fluorofucose (2FF), a fucosylation inhibitor, during cell differentiation dramatically reduced the expression of myogenic genes, such as Myomaker and other myogenic fusion genes, and inhibited myotube formation. These results indicate that Fut8 is an important factor in myogenesis, and myofusion in particular.
- Published
- 2022
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22. Myocyte Culture with Decellularized Skeletal Muscle Sheet with Observable Interaction with the Extracellular Matrix.
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Nakada S, Yamashita Y, Akiba S, Shima T, and Arikawa-Hirasawa E
- Abstract
In skeletal muscles, muscle fibers are highly organized and bundled within the basement membrane. Several microfabricated substrate models have failed to mimic the macrostructure of native muscle, including various extracellular matrix (ECM) proteins. Therefore, we developed and evaluated a system using decellularized muscle tissue and mouse myoblasts C2C12 to analyze the interaction between native ECM and myocytes. Chicken skeletal muscle was sliced into sheets and decellularized to prepare decellularized skeletal muscle sheets (DSMS). C2C12 was then seeded and differentiated on DSMS. Immunostaining for ECM molecules was performed to examine the relationship between myoblast adhesion status, myotube orientation, and collagen IV orientation. Myotube survival in long-term culture was confirmed by calcein staining. C2C12 myoblasts adhered to scaffolds in DSMS and developed adhesion plaques and filopodia. Furthermore, C2C12 myotubes showed orientation along the ECM orientation within DSMS. Compared to plastic dishes, detachment was less likely to occur on DSMS, and long-term incubation was possible. This culture technique reproduces a cell culture environment reflecting the properties of living skeletal muscle, thereby allowing studies on the interaction between the ECM and myocytes.
- Published
- 2022
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23. Impact of the heparan sulfate proteoglycan perlecan on human disease and health.
- Author
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Arikawa-Hirasawa E
- Subjects
- Animals, Extracellular Matrix Proteins, Heparan Sulfate Proteoglycans genetics, Heparan Sulfate Proteoglycans metabolism, Heparitin Sulfate, Humans, Mice, Dwarfism, Osteochondrodysplasias genetics, Osteochondrodysplasias metabolism
- Abstract
Perlecan, a basement membrane-type heparan sulfate proteoglycan, is an important molecule in the functional diversity of organisms because of the diversity of its glycan chains and the multifunctionality of its core proteins. Human diseases associated with perlecan have been identified using gene-deficient mice. Two human diseases related to perlecan have been reported. One is Silverman-Handmaker type dyssegmental dysplasia, resulting from the complete loss of function of the HSPG2 gene that encodes perlecan core protein, which is mapped to chromosome 1p36. The other is Schwartz-Jampel syndrome resulting from the partial loss of function of the HSPG2 gene. Subsequent in vivo and in vitro studies have revealed the organ-specific functions of perlecan, suggesting its involvement in the pathogenesis of various human diseases. In this review, we discuss the role of perlecan in human diseases and summarize our knowledge about perlecan as a future therapeutic target to treat related diseases and for healthy longevity.
- Published
- 2022
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24. Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain.
- Author
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Tsuji Y, Kerever A, Furukawa T, Kamagata K, Saito Y, Aoki S, Hata J, Okano H, Kobayashi K, Okada T, Miya K, Keino-Masu K, Masu M, and Arikawa-Hirasawa E
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Heparitin Sulfate, Humans, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred C57BL, Mice, Knockout, Diffusion Tensor Imaging, Sulfotransferases genetics, Sulfotransferases metabolism
- Abstract
During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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25. Increased Risk of Aortic Dissection with Perlecan Deficiency.
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Nonaka R, Iesaki T, Kerever A, and Arikawa-Hirasawa E
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Aorta ultrastructure, Biomarkers metabolism, Elasticity, Elastin metabolism, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Fibrillin-1 metabolism, Heparan Sulfate Proteoglycans metabolism, Matrix Metalloproteinases metabolism, Mice, Transgenic, Myocardial Contraction, Myocytes, Smooth Muscle metabolism, Protein Biosynthesis, RNA, Messenger genetics, RNA, Messenger metabolism, Risk Factors, Aortic Dissection metabolism, Aortic Dissection pathology, Heparan Sulfate Proteoglycans deficiency
- Abstract
Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development and maintenance of the aortic wall remains unknown. Perlecan-deficient mice ( Hspg2
-/- -Tg: Perl KO) have been found to show a high frequency (15-35%) of aortic dissection (AD). Herein, an analysis of the aortic wall of Perl KO mice revealed that perlecan deficiency caused thinner and partially torn elastic lamina. Compared to the control aortic tissue, perlecan-deficient aortic tissue showed a significant decrease in desmosine content and an increase in soluble tropoelastin levels, implying the presence of immature elastic fibers in Perl KO mice. Furthermore, the reduced expression of the smooth muscle cell contractile proteins actin and myosin in perlecan-deficient aortic tissue may explain the risk of AD. This study showed that a deficiency in perlecan, which is localized along the elastic lamina and at the interface between elastin and fibrillin-1, increased the risk of AD, largely due to the immaturity of extracellular matrix in the aortic tissue. Overall, we proposed a new model of AD that considers the deficiency of extracellular molecule perlecan as a risk factor.- Published
- 2021
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26. Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches.
- Author
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Kerever A, Nagahara F, Keino-Masu K, Masu M, van Kuppevelt TH, Vivès RR, and Arikawa-Hirasawa E
- Subjects
- Animals, Extracellular Matrix, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Neurogenesis, Stem Cell Niche, Sulfatases deficiency, Sulfotransferases deficiency, Heparitin Sulfate metabolism, Lateral Ventricles metabolism, Sulfatases metabolism, Sulfotransferases metabolism
- Abstract
Fractones, specialized extracellular matrix structures found in the subventricular zone (SVZ) neurogenic niche, can capture growth factors, such as basic fibroblast growth factor, from the extracellular milieu through a heparin-binding mechanism for neural stem cell (NSC) presentation, which promotes neurogenesis. During aging, a decline in neurogenesis correlates with a change in the composition of heparan sulfate (HS) within fractones. In this study, we used antibodies that recognize specific short oligosaccharides with varying sulfation to evaluate the HS composition in fractones in young and aged brains. To further understand the conditions that regulate 6-O sulfation levels and its impact on neurogenesis, we used endosulfatase Sulf1 and Sulf2 double knockout (DKO) mice. Fractones in the SVZ of Sulf1/2 DKO mice showed immunoreactivity for the HS epitope, suggesting higher 6-O sulfation. While neurogenesis declined in the aged SVZ of both wild-type and Sulf1/2 DKO mice, we observed a larger number of neuroblasts in the young and aged SVZ of Sulf1/2 DKO mice. Together, these results show that the removal of 6-O-sulfation in fractones HS by endosulfatases inhibits neurogenesis in the SVZ. Our findings advance the current understanding regarding the extracellular environment that is best suited for NSCs to thrive, which is critical for the design of future stem cell therapies., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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27. Optimal Extracellular Matrix Niches for Neurogenesis: Identifying Glycosaminoglycan Chain Composition in the Subventricular Neurogenic Zone.
- Author
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Kerever A and Arikawa-Hirasawa E
- Abstract
In the adult mammalian brain, new neurons are generated in a restricted region called the neurogenic niche, which refers to the specific regulatory microenvironment of neural stem cells (NSCs). Among the constituents of neurogenic niches, the extracellular matrix (ECM) has emerged as a key player in NSC maintenance, proliferation, and differentiation. In particular, heparan sulfate (HS) proteoglycans are capable of regulating various growth factor signaling pathways that influence neurogenesis. In this review, we summarize our current understanding of the ECM niche in the adult subventricular zone (SVZ), with a special focus on basement membrane (BM)-like structures called fractones, and discuss how fractones, particularly their composition of glycosaminoglycans (GAGs), may influence neurogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kerever and Arikawa-Hirasawa.)
- Published
- 2021
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28. Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy.
- Author
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Nakada S, Yamashita Y, Machida S, Miyagoe-Suzuki Y, and Arikawa-Hirasawa E
- Subjects
- Animals, Heparan Sulfate Proteoglycans pharmacology, Humans, Mice, Mice, Knockout, Heparan Sulfate Proteoglycans therapeutic use, Muscular Atrophy chemically induced, Nitric Oxide Synthase Type I drug effects
- Abstract
Perlecan is an extracellular matrix molecule anchored to the sarcolemma by a dystrophin-glycoprotein complex. Perlecan-deficient mice are tolerant to muscle atrophy, suggesting that perlecan negatively regulates mechanical stress-dependent skeletal muscle mass. Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol triggers protein degradation, thereby initiating skeletal muscle atrophy. We hypothesized that perlecan regulates nNOS delocalization and activates protein degradation during this process. To determine the role of perlecan in nNOS-mediated mechanotransduction, we used sciatic nerve transection as a denervation model of gastrocnemius muscles. Gastrocnemius muscle atrophy was significantly lower in perinatal lethality-rescued perlecan-knockout ( Hspg2
-/- -Tg mice. Moreover, levels of atrophy-related proteins-i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins-increased in the denervated muscles of WT-Tg mice but not in Hspg2-/- -Tg mice. Moreover, levels of atrophy-related proteins-i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins-increased in the denervated muscles of WT-Tg mice but not in Hspg2-/- -Tg mice. These findings suggest that during denervation, perlecan promotes nNOS delocalization from the membrane and stimulates protein degradation and muscle atrophy by activating FoxO signaling and the ubiquitin-proteasome system.- Published
- 2020
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29. A nationwide observational study of locomotive syndrome in Japan using the ResearchKit: The Locomonitor study.
- Author
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Yoshimura Y, Ishijima M, Ishibashi M, Liu L, Arikawa-Hirasawa E, Machida S, Naito H, Hamada C, and Kominami E
- Subjects
- Adult, Aged, Cross-Sectional Studies, Disability Evaluation, Female, Humans, Japan epidemiology, Male, Middle Aged, Reproducibility of Results, Syndrome, Young Adult, Locomotion, Mass Screening methods, Mobile Applications, Mobility Limitation
- Abstract
Background: We developed the Locomonitor application (app), the world's first iOS app to study locomotive syndrome, using the ResearchKit and examined the prevalence and risk factors for locomotive syndrome in Japanese general individuals 20-69 years old in a nationwide cross-sectional observational study., Methods: The participants were recruited from February to August 2016. The outcome measures for the locomotive function were evaluated by locomotive syndrome risk tests (LSRTs) using the Locomonitor app. The chi-squared test, a linear-by-linear association trend analysis, and Spearman's correlation test were performed as statistical analyses., Results: A total of 2177 subjects from all prefectures in Japan were included (average 42.2 years old). The Locomo25 and Stand-Up test scores in female participants and the Two-Step test scores in male participants showed age-dependent deterioration. In the overall population, the incidence of Locomo stage 1 and 2, as evaluated by the Locomo25, Stand-Up test or Two-Step test, was 30.2% and 29.2%, respectively. In subjects without locomotive syndrome (40.5%), LSRT scores showed age-dependent deterioration in both sexes. Locomotive syndrome in participants with a body mass index (BMI) of ≥25 kg/m
2 was more frequent than in those with a BMI of <25 kg/m2 (age- and gender-adjusted odds ratio [OR] 1.344 [95% confidence interval {CI} 1.03-1.75, p = 0.027]). Locomotive syndrome in participants with an exercise habit was less frequent than in those without an exercise habit (age- and gender-adjusted OR 0.499 [95% CI 0.33-0.755, p < 0.0001])., Conclusions: The Locomonitor app, a newly developed remote platform, revealed that approximately 20%-30% of Japanese individuals 20-69 years old in the general population met the definition of locomotive syndrome. Locomotive syndrome in participants with obesity was more frequent than those without obesity, while locomotive syndrome in participants with an exercise habit was less frequent than those without an exercise habit., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
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30. Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1.
- Author
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de Vega S, Kondo A, Suzuki M, Arai H, Jiapaer S, Sabit H, Nakada M, Ikeuchi T, Ishijima M, Arikawa-Hirasawa E, Yamada Y, and Okada Y
- Subjects
- Angiopoietin-1 metabolism, Brain Neoplasms blood supply, Brain Neoplasms metabolism, Calcium-Binding Proteins metabolism, Cells, Cultured, Coculture Techniques, Gene Expression Regulation, Neoplastic, Glioblastoma blood supply, Glioblastoma metabolism, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells physiology, Humans, Neovascularization, Pathologic metabolism, Neovascularization, Physiologic drug effects, Neovascularization, Physiologic genetics, Pericytes cytology, Pericytes drug effects, Pericytes metabolism, Protein Binding, Vascular Endothelial Growth Factor A pharmacology, Angiopoietin-1 genetics, Brain Neoplasms genetics, Calcium-Binding Proteins genetics, Glioblastoma genetics, Neovascularization, Pathologic genetics
- Abstract
Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin-7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin-1, but not angiopoietin-2 or Tie2 receptor, through interaction between the N-terminal portions of Fbln7 and angiopoietin-1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin-1 expression by HBVP. The production of aberrant VEGF-induced tube-like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N-terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin-1/angiopoietin-2-Tie2 axis., (© 2019 UICC.)
- Published
- 2019
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31. Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier.
- Author
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Nakamura K, Ikeuchi T, Nara K, Rhodes CS, Zhang P, Chiba Y, Kazuno S, Miura Y, Ago T, Arikawa-Hirasawa E, Mukouyama YS, and Yamada Y
- Subjects
- Animals, Blood-Brain Barrier pathology, Disease Models, Animal, Heparan Sulfate Proteoglycans administration & dosage, Heparan Sulfate Proteoglycans deficiency, Infarction, Middle Cerebral Artery pathology, Injections, Intraperitoneal, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Blood-Brain Barrier metabolism, Heparan Sulfate Proteoglycans metabolism, Infarction, Middle Cerebral Artery metabolism, Pericytes metabolism
- Abstract
Ischemic stroke causes blood-brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan ( Hspg2 )-deficient ( Hspg2
- / - - TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2- / - - TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)- Published
- 2019
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32. Extracellular Protein Fibulin-7 and Its C-Terminal Fragment Have In Vivo Antiangiogenic Activity.
- Author
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Ikeuchi T, de Vega S, Forcinito P, Doyle AD, Amaral J, Rodriguez IR, Arikawa-Hirasawa E, and Yamada Y
- Subjects
- Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors pharmacology, Animals, Calcium-Binding Proteins chemistry, Calcium-Binding Proteins pharmacology, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells metabolism, Extracellular Matrix Proteins chemistry, Extracellular Matrix Proteins metabolism, Extracellular Matrix Proteins pharmacology, Female, Human Umbilical Vein Endothelial Cells, Humans, Integrin alpha5beta1 metabolism, Mice, Phosphorylation drug effects, Rats, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Signal Transduction drug effects, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Angiogenesis Inhibitors metabolism, Calcium-Binding Proteins metabolism, Neovascularization, Physiologic drug effects
- Abstract
Angiogenesis is crucial for tissue development and homeostasis; however, excessive angiogenesis can lead to diseases, including arthritis and cancer metastasis. Some antiangiogenic drugs are available, but side effects remain problematic. Thus, alternative angiogenesis inhibition strategies are needed. Fibulin-7 (Fbln7) is a newly discovered member of the fibulin protein family, a group of cell-secreted glycoproteins, that functions as a cell adhesion molecule and interacts with other extracellular matrix (ECM) proteins as well as cell receptors. We previously showed that a recombinant C-terminal Fbln7 fragment (Fbln7-C) inhibits tube formation by human umbilical vein endothelial cells (HUVECs) in vitro. In the present study, we examined the in vivo antiangiogenic activity of recombinant full-length Fbln7 (Fbln7-FL) and Fbln7-C proteins using a rat corneal angiogenesis model. We found that both Fbln7-FL and Fbln7-C inhibited neovascularization. Fbln7-C bound to vascular endothelial growth factor receptor 2 (VEGFR2), inhibiting VEGFR2 and ERK phosphorylation and resulting in reduced HUVEC motility. HUVEC attachment to Fbln7-C occurred through an interaction with integrin α5β1 and regulated changes in cellular morphology. These results suggest that Fbln7-C action may target neovascularization by altering cell/ECM associations. Therefore, Fbln7-C could have potential as a therapeutic agent for diseases associated with angiogenesis.
- Published
- 2018
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33. Perlecan, a heparan sulfate proteoglycan, regulates systemic metabolism with dynamic changes in adipose tissue and skeletal muscle.
- Author
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Yamashita Y, Nakada S, Yoshihara T, Nara T, Furuya N, Miida T, Hattori N, and Arikawa-Hirasawa E
- Subjects
- Animals, Glucose metabolism, Heparan Sulfate Proteoglycans genetics, Heparan Sulfate Proteoglycans metabolism, Lipid Metabolism, Metabolic Syndrome metabolism, Mice, Knockout, Obesity genetics, Obesity metabolism, Obesity pathology, Physical Conditioning, Animal, Adipose Tissue metabolism, Energy Metabolism physiology, Heparan Sulfate Proteoglycans physiology, Muscle, Skeletal metabolism
- Abstract
Perlecan (HSPG2), a heparan sulfate proteoglycan, is a component of basement membranes and participates in a variety of biological activities. Here, we show physiological roles of perlecan in both obesity and the onset of metabolic syndrome. The perinatal lethality-rescued perlecan knockout (Hspg2
-/- -Tg) mice showed a smaller mass and cell size of white adipose tissues than control (WT-Tg) mice. Abnormal lipid deposition, such as fatty liver, was not detected in the Hspg2-/- -Tg mice, and those mice also consumed more fat as an energy source, likely due to their activated fatty acid oxidation. In addition, the Hspg2-/- -Tg mice demonstrated increased insulin sensitivity. Molecular analysis revealed the significantly relatively increased amount of the muscle fiber type IIA (X) isoform and a larger quantity of mitochondria in the skeletal muscle of Hspg2-/- -Tg mice. Furthermore, the perlecan-deficient skeletal muscle also had elevated levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) protein. PGC1α expression is activated by exercise, and induces mitochondrial biosynthesis. Thus, perlecan may act as a mechano-regulator of catabolism of both lipids and glucose by shifting the muscle fiber composition to oxidative fibers. Our data suggest that downregulation of perlecan is a promising strategy to control metabolic syndrome.- Published
- 2018
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34. The Relationship between Neurite Density Measured with Confocal Microscopy in a Cleared Mouse Brain and Metrics Obtained from Diffusion Tensor and Diffusion Kurtosis Imaging.
- Author
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Irie R, Kamagata K, Kerever A, Ueda R, Yokosawa S, Otake Y, Ochi H, Yoshizawa H, Hayashi A, Tagawa K, Okazawa H, Takahashi K, Sato K, Hori M, Arikawa-Hirasawa E, and Aoki S
- Subjects
- Animals, Anisotropy, Diffusion, Mice, Water, Brain cytology, Brain pathology, Diffusion Tensor Imaging methods, Microscopy, Confocal methods, Neurites chemistry
- Abstract
Purpose: Diffusional kurtosis imaging (DKI) enables sensitive measurement of tissue microstructure by quantifying the non-Gaussian diffusion of water. Although DKI is widely applied in many situations, histological correlation with DKI analysis is lacking. The purpose of this study was to determine the relationship between DKI metrics and neurite density measured using confocal microscopy of a cleared mouse brain., Methods: One thy-1 yellow fluorescent protein 16 mouse was deeply anesthetized and perfusion fixation was performed. The brain was carefully dissected out and whole-brain MRI was performed using a 7T animal MRI system. DKI and diffusion tensor imaging (DTI) data were obtained. After the MRI scan, brain sections were prepared and then cleared using aminoalcohols (CUBIC). Confocal microscopy was performed using a two-photon confocal microscope with a laser. Forty-eight ROIs were set on the caudate putamen, seven ROIs on the anterior commissure, and seven ROIs on the ventral hippocampal commissure on the confocal microscopic image and a corresponding MR image. In each ROI, histological neurite density and the metrics of DKI and DTI were calculated. The correlations between diffusion metrics and neurite density were analyzed using Pearson correlation coefficient analysis., Results: Mean kurtosis (MK) (P = 5.2 × 10
-9 , r = 0.73) and radial kurtosis (P = 2.3 × 10-9 , r = 0.74) strongly correlated with neurite density in the caudate putamen. The correlation between fractional anisotropy (FA) and neurite density was moderate (P = 0.0030, r = 0.42). In the anterior commissure and the ventral hippocampal commissure, neurite density and FA are very strongly correlated (P = 1.3 × 10-5 , r = 0.90). MK in these areas were very high value and showed no significant correlation (P = 0.48)., Conclusion: DKI accurately reflected neurite density in the area with crossing fibers, potentially allowing evaluation of complex microstructures.- Published
- 2018
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35. Altered expression of laminin alpha1 in aganglionic colon of endothelin receptor-B null mouse model of Hirschsprung's disease.
- Author
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Fujiwara N, Nakazawa-Tanaka N, Miyahara K, Arikawa-Hirasawa E, Akazawa C, and Yamataka A
- Subjects
- Animals, Cell Differentiation, Cell Movement physiology, Colon innervation, Colon pathology, Disease Models, Animal, Enteric Nervous System metabolism, Enteric Nervous System pathology, Female, Hirschsprung Disease metabolism, Hirschsprung Disease pathology, Laminin biosynthesis, Male, Mice, Mice, Knockout, Microscopy, Confocal, Real-Time Polymerase Chain Reaction, Receptor, Endothelin B biosynthesis, Colon metabolism, Gene Expression Regulation, Hirschsprung Disease genetics, Laminin genetics, RNA genetics, Receptor, Endothelin B genetics
- Abstract
Purpose: Laminin, an extracellular matrix molecule, is essential for normal development of the nervous system. The alpha1 subunit of laminin-1 (LAMA1) has been reported to promote neurites and outgrowth and is expressed only during embryogenesis. Previously, we developed a Sox10 transgenic version of the Endothelin receptor-B (Ednrb) mouse to visualize Enteric neural crest-derived cell (ENCC)s with a green fluorescent protein, Venus. We designed this study to investigate the expression of LAMA1 using Sox10-VENUS mice gut., Methods: We harvested the gut on days 13.5 (E13.5) and 15.5 (E15.5) of gestation. Sox10-VENUS
+ /Ednrb-/- mice (n = 8) were compared with Sox10-VENUS+ /Ednrb+/+ mice (n = 8) as controls. Gene expression of LAMA1 was analysed by real-time RT-PCR. Fluorescent immunohistochemistry was performed to assess protein distribution., Results: The relative mRNA expression levels of LAMA1 were significantly increased in HD in the proximal and distal colon on E15.5 compared to controls (p < 0.05), whereas there were no significant differences on E13.5. LAMA1 was expressed in the serosa, submucosa and basal lamina in the gut, and was markedly increased in the proximal and distal colon of HD on E15.5., Conclusions: Altered LAMA1 expression in the aganglionic region may contribute to impaired ENCC migration, resulting in HD. These data could help in understanding the pathophysiologic interactions between LAMA1 and ENCC migration.- Published
- 2018
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36. Heparan sulfate alterations in extracellular matrix structures and fibroblast growth factor-2 signaling impairment in the aged neurogenic niche.
- Author
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Yamada T, Kerever A, Yoshimura Y, Suzuki Y, Nonaka R, Higashi K, Toida T, Mercier F, and Arikawa-Hirasawa E
- Subjects
- Aging drug effects, Animals, Extracellular Matrix metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Heparitin Sulfate metabolism, Male, Mice, Inbred C57BL, Aging physiology, Cell Proliferation drug effects, Fibroblast Growth Factor 2 metabolism, Heparitin Sulfate pharmacology, Lateral Ventricles drug effects, Neurogenesis drug effects, Signal Transduction drug effects
- Abstract
Adult neurogenesis in the subventricular zone of the lateral ventricle decreases with age. In the subventricular zone, the specialized extracellular matrix structures, known as fractones, contact neural stem cells and regulate neurogenesis. Fractones are composed of extracellular matrix components, such as heparan sulfate proteoglycans. We previously found that fractones capture and store fibroblast growth factor 2 (FGF-2) via heparan sulfate binding, and may deliver FGF-2 to neural stem cells in a timely manner. The heparan sulfate (HS) chains in the fractones of the aged subventricular zone are modified based on immunohistochemistry. However, how aging affects fractone composition and subsequent FGF-2 signaling and neurogenesis remains unknown. The formation of the FGF-fibroblast growth factor receptor-HS complex is necessary to activate FGF-2 signaling and induce the phosphorylation of extracellular signal-regulated kinase (Erk1/2). In this study, we observed a reduction in HS 6-O-sulfation, which is critical for FGF-2 signal transduction, and failure of the FGF-2-induced phosphorylation of Erk1/2 in the aged subventricular zone. In addition, we observed increased HS 6-O-endo-sulfatase, an enzyme that may be responsible for the HS modifications in aged fractones. In conclusion, the data revealed that heparan sulfate 6-O-sulfation is reduced and FGF-2-dependent Erk1/2 signaling is impaired in the aged subventricular zone. HS modifications in fractones might play a role in the reduced neurogenic activity in aging brains., (© 2017 International Society for Neurochemistry.)
- Published
- 2017
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37. Understanding microstructure of the brain by comparison of neurite orientation dispersion and density imaging (NODDI) with transparent mouse brain.
- Author
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Sato K, Kerever A, Kamagata K, Tsuruta K, Irie R, Tagawa K, Okazawa H, Arikawa-Hirasawa E, Nitta N, Aoki I, and Aoki S
- Abstract
Background: Neurite orientation dispersion and density imaging (NODDI) is a diffusion magnetic resonance imaging (MRI) technique with the potential to visualize the microstructure of the brain. Revolutionary histological methods to render the mouse brain transparent have recently been developed, but verification of NODDI by these methods has not been reported., Purpose: To confirm the concordance of NODDI with histology in terms of density and orientation dispersion of neurites of the brain., Material and Methods: Whole brain diffusion MRI of a thy-1 yellow fluorescent protein mouse was acquired with a 7-T MRI scanner, after which transparent brain sections were created from the same mouse. NODDI parameters calculated from the MR images, including the intracellular volume fraction (Vic) and the orientation dispersion index (ODI), were compared with histological findings. Neurite density, Vic, and ODI were compared between areas of the anterior commissure and the hippocampus containing crossing fibers (crossing areas) and parallel fibers (parallel areas), and the correlation between fiber density and Vic was assessed., Results: The ODI was significantly higher in the crossing area compared to the parallel area in both the anterior commissure and the hippocampus ( P = 0.0247, P = 0.00022, respectively). Neurite density showed a similar tendency, but was significantly different only in the hippocampus ( P = 7.91E-07). There was no significant correlation between neurite density and Vic., Conclusion: NODDI was verified by histology for quantification of the orientation dispersion of neurites. These results indicate that the ODI is a suitable index for understanding the microstructure of the brain in vivo .
- Published
- 2017
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38. Perlecan is required for the chondrogenic differentiation of synovial mesenchymal cells through regulation of Sox9 gene expression.
- Author
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Sadatsuki R, Kaneko H, Kinoshita M, Futami I, Nonaka R, Culley KL, Otero M, Hada S, Goldring MB, Yamada Y, Kaneko K, Arikawa-Hirasawa E, and Ishijima M
- Subjects
- Adipogenesis, Animals, Cartilage metabolism, Cell Differentiation, Cell Proliferation, Cells, Cultured, Core Binding Factor Alpha 1 Subunit metabolism, Female, Gene Expression Regulation, Mice, Mice, Knockout, Osteogenesis, PPAR gamma metabolism, Chondrocytes cytology, Chondrogenesis physiology, Heparan Sulfate Proteoglycans metabolism, Mesenchymal Stem Cells cytology, SOX9 Transcription Factor metabolism, Synovial Membrane metabolism
- Abstract
We previously reported that perlecan, a heparan-sulfate proteoglycan (Hspg2), expressed in the synovium at the cartilage-synovial junction, is required for osteophyte formation in knee osteoarthritis. To examine the mechanism underlying this process, we examined the role of perlecan in the proliferation and differentiation of synovial mesenchymal cells (SMCs), using a recently established mouse synovial cell culture method. Primary SMCs isolated from Hspg2
-/- -Tg (Hspg2-/- ;Col2a1-Hspg2Tg/- ) mice, in which the perlecan-knockout was rescued from perinatal lethality, lack perlecan. The chondrogenic-, osteogenic-, and adipogenic-potentials were examined in the Hspg2-/- -Tg SMCs compared to the control SMCs prepared from wild-type Hspg2+/+ -Tg (Hspg2+/+ ;Col2a1-Hspg2Tg/- ) littermates. In a culture condition permitting proliferation, both control and Hspg2-/- -Tg SMCs showed similar rates of proliferation and expression of cell surface markers. However, in micromass cultures, the cartilage matrix production and Sox9 and Col2a1 mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs, compared with control SMCs. The reduced level of Sox9 mRNA was restored by the supplementation with exogenous perlecan protein. There was no difference in osteogenic differentiation between the control and Hspg2-/- -Tg SMCs, as measured by the levels of Runx2 and Col1a1 mRNA. The adipogenic induction and PPARγ mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs compared to control SMCs. The reduction of PPARγ mRNA levels in Hspg2-/- -Tg SMCs was restored by supplementation of perlecan. Perlecan is required for the chondrogenic and adipogenic differentiation from SMCs via its regulation of the Sox9 and PPARγ gene expression, but not for osteogenic differentiation via Runx2. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:837-846, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)- Published
- 2017
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39. Quantitative Histological Validation of Diffusion Tensor MRI with Two-Photon Microscopy of Cleared Mouse Brain.
- Author
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Kamagata K, Kerever A, Yokosawa S, Otake Y, Ochi H, Hori M, Kamiya K, Tsuruta K, Tagawa K, Okazawa H, Aoki S, and Arikawa-Hirasawa E
- Published
- 2016
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40. Identification of peptides derived from the C-terminal domain of fibulin-7 active for endothelial cell adhesion and tube formation disruption.
- Author
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de Vega S, Hozumi K, Suzuki N, Nonaka R, Seo E, Takeda A, Ikeuchi T, Nomizu M, Yamada Y, and Arikawa-Hirasawa E
- Abstract
Despite the research done on pathological angiogenesis, there is still a need for the development of new therapies against angiogenesis-related diseases. Fibulin-7 (Fbln7) is a member of the extracellular matrix fibulin protein family. The Fbln7 C-terminal fragment, Fbln7-C, binds to endothelial cells and inhibits their tube formation in culture. In this study, we screened 12 synthetic peptides, covering the fibulin-globular domain of Fbln7-C, to identify active sites for endothelial cell adhesion and in vitro antiangiogenic activity. Three peptides, fc10, fc11, and fc12, promoted Human Umbilical Vein Endothelial Cells (HUVECs) adhesion, and the morphology of HUVECs on fc10 was similar to that on Fbln7-C. EDTA and the anti-integrin β1 function-blocking antibody inhibited HUVECs adhesion to both fc10 and fc12, and heparin inhibited HUVECs adhesion to both fc11 and fc12. fc10 and fc11 inhibited HUVECs tube formation. Our results suggest that three peptides from Fbln7-C are biologically active for endothelial cell adhesion and disrupt the tube formation, suggesting a potential therapeutic use of these peptides for angiogenesis-related diseases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 184-195, 2016., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
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41. Perlecan inhibits autophagy to maintain muscle homeostasis in mouse soleus muscle.
- Author
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Ning L, Xu Z, Furuya N, Nonaka R, Yamada Y, and Arikawa-Hirasawa E
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Animals, Collagen Type II genetics, Collagen Type II metabolism, Gene Expression Regulation, Genes, Reporter, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Heparan Sulfate Proteoglycans deficiency, Homeostasis genetics, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Multiprotein Complexes genetics, Multiprotein Complexes metabolism, Muscle Fibers, Fast-Twitch pathology, Muscle, Skeletal pathology, Muscular Atrophy metabolism, Muscular Atrophy pathology, Phosphorylation, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Ribosomal Protein S6 Kinases, 70-kDa genetics, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Signal Transduction, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tenotomy, Autophagy genetics, Heparan Sulfate Proteoglycans genetics, Muscle Fibers, Fast-Twitch metabolism, Muscle, Skeletal metabolism, Muscular Atrophy genetics
- Abstract
The autophagy-lysosome system is essential for muscle protein synthesis and degradation equilibrium, and its dysfunction has been linked to various muscle disorders. It has been reported that a diverse collection of extracellular matrix constituents, including decorin, collagen VI, laminin α2, endorepellin, and endostatin, can modulate autophagic signaling pathways. However, the association between autophagy and perlecan in muscle homeostasis remains unclear. The mechanical unloading of perlecan-deficient soleus muscles resulted in significantly decreased wet weights and cross-section fiber area compared with those of control mice. We found that perlecan deficiency in slow-twitch soleus muscles enhanced autophagic activity. This was accompanied by a decrease in autophagic substrates, such as p62, and an increase in LC3II levels. Furthermore, perlecan deficiency caused a reduction in the phosphorylation levels of p70S6k and Akt and increased the phosphorylation of AMPKα. Our findings suggested that perlecan inhibits the autophagic process through the activation of the mTORC1 pathway. This autophagic response may be a novel target for enhancing the efficacy of skeletal muscle atrophy treatment., (Copyright © 2015. Published by Elsevier B.V.)
- Published
- 2015
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42. A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space.
- Author
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Iwata S, Ito M, Nakata T, Noguchi Y, Okuno T, Ohkawara B, Masuda A, Goto T, Adachi M, Osaka H, Nonaka R, Arikawa-Hirasawa E, and Ohno K
- Subjects
- Asian People, Child, Extracellular Space, HEK293 Cells, Humans, Japan, Male, Muscle, Skeletal pathology, Mutation, Missense, Osteochondrodysplasias metabolism, Heparan Sulfate Proteoglycans genetics, Heparan Sulfate Proteoglycans metabolism, Osteochondrodysplasias genetics
- Abstract
Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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43. Fractone aging in the subventricular zone of the lateral ventricle.
- Author
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Kerever A, Yamada T, Suzuki Y, Mercier F, and Arikawa-Hirasawa E
- Subjects
- Animals, Extracellular Matrix chemistry, Heparitin Sulfate metabolism, Immunohistochemistry, Lateral Ventricles metabolism, Mice, Microscopy, Confocal, Neural Stem Cells cytology, Real-Time Polymerase Chain Reaction, Stem Cell Niche physiology, Aging pathology, Extracellular Matrix pathology, Lateral Ventricles pathology, Neurogenesis physiology
- Abstract
In adulthood, the subventricular zone (SVZ) is one of the restricted places where neurogenesis persists. In this neurogenic niche, specialized extracellular matrix (ECM) structures termed fractones contact neural stem cells and their immediate progeny. Fractones are composed of ubiquitous ECM components including heparan sulfate proteoglycans such as perlecan and agrin. We have previously shown that fractones can capture growth factors and promote growth factor activity through a heparin binding mechanism in order to regulate neurogenesis. With aging, neurogenesis is known to decrease. However, the effect of aging on fractones structure and composition remains unknown. Here, we report that, while fractone number decreased, fractone size dramatically increased with aging. Despite the changes in fractones morphology, niche cells expressing glial fibrillary acidic protein kept direct contact with fractones. Furthermore, we have observed that heparan sulfate chains contained in fractones were modified with aging. However, FGF-2 was still captured by fractones via heparan sulfates. Together, our results suggest that the changes observed in fractones structure and composition are critically related to aging of the SVZ neurogenic niche., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
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44. Perlecan deficiency causes endothelial dysfunction by reducing the expression of endothelial nitric oxide synthase.
- Author
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Nonaka R, Iesaki T, de Vega S, Daida H, Okada T, Sasaki T, and Arikawa-Hirasawa E
- Abstract
Perlecan is a major heparan sulfate proteoglycan found in the subendothelial extracellular matrix of the vascular wall. The aim of this study was to investigate the role of perlecan in the regulation of vascular tone. A previously developed conditional perlecan-deficient mouse model was used to measure changes in the isometric force of isolated aortic rings. The vessels were first precontracted with phenylephrine, and then treated with increasing concentrations of vasorelaxants. Endothelium-dependent relaxation, elicited by acetylcholine, was significantly reduced in the perlecan-deficient aortas, whereas endothelium-independent relaxation caused by the exogenous nitric oxide donor sodium nitroprusside remained well preserved. The expression of the endothelial nitric oxide synthase (eNOS) gene, detected by real-time polymerase chain reaction, was significantly decreased in the perlecan-deficient aortas. The expression of eNOS protein detected using Western blotting was also significantly decreased in the perlecan-deficient aortas. We examined the role of perlecan in eNOS gene expression by creating perlecan knockdown human aortic endothelial cells using small interfering RNA (siRNA) for perlecan. Perlecan gene expression was significantly reduced in the perlecan siRNA-treated cells, resulting in a significant decrease in eNOS gene expression. Perlecan deficiency induced endothelial dysfunction, as indicated by a reduction in endothelium-dependent relaxation due, at least partly, to a reduction in eNOS expression. These findings suggest that perlecan plays a role in the activation of eNOS gene expression during normal growth processes., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
45. See-through Brains and Diffusion Tensor MRI Clarified Fiber Connections: A Preliminary Microstructural Study in a Mouse with Callosal Agenesis.
- Author
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Kerever A, Kamagata K, Yokosawa S, Otake Y, Ochi H, Yamada T, Hori M, Kamiya K, Nishikori A, Aoki S, and Arikawa-Hirasawa E
- Subjects
- Animals, Brain abnormalities, Brain anatomy & histology, Corpus Callosum pathology, Disease Models, Animal, Fornix, Brain pathology, Hippocampus pathology, Histocytological Preparation Techniques methods, Image Processing, Computer-Assisted methods, Imaging, Three-Dimensional methods, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Microtomy methods, Nerve Net pathology, Third Ventricle pathology, Tissue Fixation methods, White Matter pathology, Agenesis of Corpus Callosum pathology, Brain pathology, Diffusion Magnetic Resonance Imaging methods, Diffusion Tensor Imaging methods
- Abstract
Clearing methods that render the brain optically transparent allow high-resolution three-dimensional (3D) imaging of neural networks. We used diffusion tensor imaging (DTI) and two-photon imaging of cleared brains to analyze white matter in BTBR mice. We confirmed corpus callosum agenesis and identified an abnormal commissure close to the third ventricle. DTI and cleared-brain two-photon imaging revealed that these commissural fibers constituted a frontal clustering of the ventral hippocampal commissure and provided a detailed assessment of white matter structure in mice.
- Published
- 2015
- Full Text
- View/download PDF
46. Laminin α1 regulates age-related mesangial cell proliferation and mesangial matrix accumulation through the TGF-β pathway.
- Author
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Ning L, Kurihara H, de Vega S, Ichikawa-Tomikawa N, Xu Z, Nonaka R, Kazuno S, Yamada Y, Miner JH, and Arikawa-Hirasawa E
- Subjects
- Aging genetics, Aging pathology, Animals, Extracellular Matrix genetics, Extracellular Matrix pathology, Glomerular Mesangium pathology, Glomerulonephritis genetics, Glomerulonephritis metabolism, Glomerulonephritis pathology, Laminin genetics, Mice, Mice, Knockout, Phosphorylation genetics, Proteinuria genetics, Proteinuria metabolism, Proteinuria pathology, Signal Transduction genetics, Smad2 Protein genetics, Smad2 Protein metabolism, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Aging metabolism, Cell Proliferation, Extracellular Matrix metabolism, Glomerular Mesangium metabolism, Laminin metabolism
- Abstract
Laminin α1 (LAMA1), a subunit of the laminin-111 basement membrane component, has been implicated in various biological functions in vivo and in vitro. Although LAMA1 is present in kidney, its roles in the kidney are unknown because of early embryonic lethality. Herein, we used a viable conditional knockout mouse model with a deletion of Lama1 in the epiblast lineage (Lama1(CKO)) to study the role of LAMA1 in kidney development and function. Adult Lama1(CKO) mice developed focal glomerulosclerosis and proteinuria with age. In addition, mesangial cell proliferation was increased, and the mesangial matrix, which normally contains laminin-111, was greatly expanded. In vitro, mesangial cells from Lama1(CKO) mice exhibited significantly increased proliferation compared with those from controls. This increased proliferation was inhibited by the addition of exogenous LAMA1-containing laminin-111, but not by laminin-211 or laminin-511, suggesting a specific role for LAMA1 in regulating mesangial cell behavior. Moreover, the absence of LAMA1 increased transforming growth factor (TGF)-β1-induced Smad2 phosphorylation, and inhibitors of TGF-β1 receptor I kinase blocked Smad2 phosphorylation in both control and Lama1(CKO) mesangial cells, indicating that the increased Smad2 phosphorylation occurred in the absence of LAMA1 via the TGF-β1 receptor. These findings suggest that LAMA1 plays a critical role in kidney function and kidney aging by regulating the mesangial cell population and mesangial matrix deposition through TGF-β/Smad signaling., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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47. PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation.
- Author
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Furuya N, Ikeda S, Sato S, Soma S, Ezaki J, Oliva Trejo JA, Takeda-Ezaki M, Fujimura T, Arikawa-Hirasawa E, Tada N, Komatsu M, Tanaka K, Kominami E, Hattori N, and Ueno T
- Subjects
- Active Transport, Cell Nucleus, Animals, Autophagy physiology, Enzyme Activation, Mice, Mice, Knockout, Ubiquitin metabolism, Autophagy genetics, Mitochondria metabolism, Mitophagy physiology, Muscular Atrophy metabolism, NF-E2-Related Factor 1 metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin-proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we show that an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress and accumulation of PARK2/Parkin, which participates in mitochondrial quality control (PARK2-mediated mitophagy), in mitochondria. Soleus muscles from denervated Park2 knockout mice also showed resistance to denervation, reduced mitochondrial activities, and increased oxidative stress. In both autophagy-deficient and Park2-deficient soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Park2-deficient mice. These results suggest that PARK2-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.
- Published
- 2014
- Full Text
- View/download PDF
48. Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling.
- Author
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Suzuki N, Numakawa T, Chou J, de Vega S, Mizuniwa C, Sekimoto K, Adachi N, Kunugi H, Arikawa-Hirasawa E, Yamada Y, and Akazawa C
- Subjects
- Animals, Base Sequence, DNA Primers, Mice, Reverse Transcriptase Polymerase Chain Reaction, Focal Adhesion Protein-Tyrosine Kinases metabolism, Membrane Proteins physiology, Neurites, Signal Transduction
- Abstract
Teneurin-4 (Ten-4), a transmembrane protein, is highly expressed in the central nervous system; however, its cellular and molecular function in neuronal differentiation remains unknown. In this study, we aimed to elucidate the function of Ten-4 in neurite outgrowth. Ten-4 expression was induced during neurite outgrowth of the neuroblastoma cell line Neuro-2a. Ten-4 protein was localized at the neurite growth cones. Knockdown of Ten-4 expression in Neuro-2a cells decreased the formation of the filopodia-like protrusions and the length of individual neurites. Conversely, overexpression of Ten-4 promoted filopodia-like protrusion formation. In addition, knockdown and overexpression of Ten-4 reduced and elevated the activation of focal adhesion kinase (FAK) and Rho-family small GTPases, Cdc42 and Rac1, key molecules for the membranous protrusion formation downstream of FAK, respectively. Inhibition of the activation of FAK and neural Wiskott-Aldrich syndrome protein (N-WASP), which is a downstream regulator of FAK and Cdc42, blocked protrusion formation by Ten-4 overexpression. Further, Ten-4 colocalized with phosphorylated FAK in the filopodia-like protrusion regions. Together, our findings show that Ten-4 is a novel positive regulator of cellular protrusion formation and neurite outgrowth through the FAK signaling pathway.
- Published
- 2014
- Full Text
- View/download PDF
49. Perlecan is required for FGF-2 signaling in the neural stem cell niche.
- Author
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Kerever A, Mercier F, Nonaka R, de Vega S, Oda Y, Zalc B, Okada Y, Hattori N, Yamada Y, and Arikawa-Hirasawa E
- Subjects
- Animals, Cell Differentiation physiology, Cell Growth Processes physiology, Heparan Sulfate Proteoglycans deficiency, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Neural Stem Cells cytology, Neurogenesis physiology, Neurons cytology, Neurons drug effects, Signal Transduction, Stem Cell Niche drug effects, Fibroblast Growth Factor 2 pharmacology, Heparan Sulfate Proteoglycans metabolism, Neural Stem Cells metabolism, Neurons metabolism, Stem Cell Niche physiology
- Abstract
In the adult subventricular zone (neurogenic niche), neural stem cells double-positive for two markers of subsets of neural stem cells in the adult central nervous system, glial fibrillary acidic protein and CD133, lie in proximity to fractones and to blood vessel basement membranes, which contain the heparan sulfate proteoglycan perlecan. Here, we demonstrate that perlecan deficiency reduces the number of both GFAP/CD133-positive neural stem cells in the subventricular zone and new neurons integrating into the olfactory bulb. We also show that FGF-2 treatment induces the expression of cyclin D2 through the activation of the Akt and Erk1/2 pathways and promotes neurosphere formation in vitro. However, in the absence of perlecan, FGF-2 fails to promote neurosphere formation. These results suggest that perlecan is a component of the neurogenic niche that regulates FGF-2 signaling and acts by promoting neural stem cell self-renewal and neurogenesis., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
50. A C-terminal fragment of fibulin-7 interacts with endothelial cells and inhibits their tube formation in culture.
- Author
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de Vega S, Suzuki N, Nonaka R, Sasaki T, Forcinito P, Arikawa-Hirasawa E, and Yamada Y
- Subjects
- Animals, Calcium-Binding Proteins chemistry, Cell Adhesion, Crk-Associated Substrate Protein metabolism, Enzyme Activation, Focal Adhesions metabolism, Focal Adhesions ultrastructure, Human Umbilical Vein Endothelial Cells cytology, Humans, Integrins metabolism, Mice, Phosphorylation, Protein Binding, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Stress Fibers metabolism, rac1 GTP-Binding Protein metabolism, rhoA GTP-Binding Protein metabolism, Calcium-Binding Proteins metabolism, Human Umbilical Vein Endothelial Cells metabolism, Neovascularization, Physiologic
- Abstract
We have previously demonstrated that fibulin-7 (Fbln7) is expressed in teeth by pre-odontoblast and odontoblast cells, localized in the basement membrane and dentin matrices, and is an adhesion molecule for dental mesenchyme cells and odontoblasts. Fbln7 is also expressed in blood vessels by endothelial cells. In this report, we show that a recombinant C-terminal Fbln7 fragment (Fbln7-C) bound to Human Umbilical Vein Endothelial Cells (HUVECs) but did not promote cell spreading and actin stress fiber formation. Fbln7-C binding to HUVECs induced integrin clustering at cell adhesion sites with other focal adhesion molecules, and sustained activation of FAK, p130Cas, and Rac1. In addition, RhoA activation was inhibited, thereby preventing HUVEC spreading. As endothelial cell spreading is an important step for angiogenesis, we examined the effect of Fbln7-C on angiogenesis using in vitro assays for endothelial cell tube formation and vessel sprouting from aortic rings. We found that Fbln7-C inhibited the HUVEC tube formation and the vessel sprouting in aortic ring assays. Our findings suggest potential anti-angiogenic activity of the Fbln7 C-terminal region., (Published by Elsevier Inc.)
- Published
- 2014
- Full Text
- View/download PDF
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