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Tatsushi Toda - One of the best experts on this subject based on the ideXlab platform.
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Effects of fukutin deficiency in the developing mouse brain
Neuromuscular Disorders, 2005Co-Authors: Tomohiro Chiyonobu, Junko Sasaki, Yoshitaka Nagai, Satoshi Takeda, Hiroshi Funakoshi, Toshikazu Nakamura, Tohru Sugimoto, Tatsushi TodaAbstract:Abstract The major pathological change in Fukuyama-type congenital muscular dystrophy brain is polymicrogyria. Pathological studies of Fukuyama-type congenital muscular dystrophy brain indicated that protrusion of neurons into the subarachnoid space through breaches in the Glia limitans–basal lamina complex is a cardinal pathogenic process in this condition. It remains undetermined, however, whether the defect causing this abnormal migration resides in the migrating neurons or in the Glia limitans–basal lamina complex. To elucidate the pathogenesis of brain abnormalities in Fukuyama-type congenital muscular dystrophy, we analyzed histologically and immunohistochemically the developing forebrain in fukutin-deficient chimeric mice and compared it with that in controls ( n =4 in each group). In chimeric embryos, ectopia became apparent as early as embryonic day 14, and laminar organization became progressively distorted. The basal lamina of the cortical surface in chimeras showed defects at E14, coinciding with the earliest time point at which ectopia were detected. Immunohistochemical analysis of glycosylated α-dystroglycan showed progressive defects coincidental with the disruption of the basal lamina. Neuronal migration was not affected in chimeras, as determined by detection of bromodeoxyuridine-labeled neurons. Extension of radial Glial fibers was intact in chimeras. Taken together, disruption of the basal lamina, caused by the loss of interaction between hypoglycosylated α-dystroglycan and its ligands, plays a key role in the pathogenesis of cortical dysplasia in Fukuyama-type congenital muscular dystrophy.
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Neuronal expression of the fukutin gene
Human Molecular Genetics, 2000Co-Authors: Junko Sasaki, Eri Kondo-iida, Kazuhiro Kobayashi, Yusuke Nakamura, Sachio Takashima, Kinya Ishikawa, Masahisa Fukayama, Hidehiro Mizusawa, Yoichi Sakakihara, Tatsushi TodaAbstract:Fukuyama-type congenital muscular dystrophy (FCMD), a relatively common autosomal recessive disorder in Japan, is characterized by severe congenital muscular dystrophy in combination with cortical dysgenesis (polymicrogyria). The gene responsible for FCMD encodes a novel protein, fukutin, which is likely to be an extracellular protein. Pathological study of brain tissue from FCMD fetuses revealed frequent breaks in the Glia limitans and basement membrane complex. Disruption of the basal lamina in FCMD muscle was also seen. Thus, structural alteration of the basal lamina appears to play a key role in the pathophysiology of FCMD. To investigate the role of fukutin in brain anomalies, we examined fukutin mRNA expression in the human brain. Northern blot and RT-PCR analysis revealed that the fukutin gene is expressed at similar levels in fetal and adult brain, whereas its expression is much reduced in FCMD brains. Tissue in situ hybridization analysis revealed fukutin mRNA expression in the migrating neurons, including Cajar-Retzius cells and adult cortical neurons, as well as in hippocampal pyramidal cells and cerebellar Purkinje cells. However, we observed no expression in the Glia limitans, the subpial astrocytes (which contribute to basement membrane formation) or other Glial cells. In the FCMD brain, neurons in regions with no dysplasia showed fair expression, whereas transcripts were nearly undetectable in the overmigrated dysplastic region. These observations suggest that fukutin function may influence neuronal migration itself rather than formation of the basement membrane. Furthermore, differences in mRNA levels among neurons in early developmental stages may partially differentiate normal and abnormal regions.
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Are breaches in the Glia limitans the primary cause of the micropolygyria in Fukuyama-type congenital muscular dystrophy (FCMD)? Pathological study of the cerebral cortex of an FCMD fetus.
Acta Neuropathologica, 1996Co-Authors: Imaharu Nakano, Masuko Funahashi, Kuniyasu Takada, Tatsushi TodaAbstract:A light and electron microscopic study of the brain of an 18-week fetus with a prenatal genetic diagnosis of Fukuyama-type congenital muscular dystrophy revealed a widespread mantle of abnormal neurogliomesenchymal tissue that covered a dysplastic cerebral cortex. In this area alone, the Glia limitans that adjoined the abnormal mantle via one or two layers of basal lamina had frequent breaches, through which neuroGlial elements extruded. In the most severely affected cortical region, which had only a rudimentary and fragmentary Glia limitans, the majority of cortical neurons had migrated into the neurogliomesenchymal tissue. The massive overmigrated neurons still maintained a somewhat columnar arrangement, and the marked dysplasia abruptly shifted to a neurogliomesenchymal tissue-free normal cortical structure with an intact Glia limitans, thus indicating essentially vertical overmigration of neurons without significant tangential migration of them. Together the above findings imply that breaches in the Glia limitans may be the primary cause of the micropolygyria seen in this genetic disorder.
Dale A Pelligrino - One of the best experts on this subject based on the ideXlab platform.
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Interactions between adenosine and K+ channel-related pathways in the coupling of somatosensory activation and pial arteriolar dilation.
American Journal of Physiology-heart and Circulatory Physiology, 2010Co-Authors: Chanannait Paisansathan, Francesco Vetri, Moises Hernandez, Haoliang Xu, Dale A PelligrinoAbstract:Multiple, perhaps interactive, mechanisms participate in the linkage between increased neural activity and cerebral vasodilation. In the present study, we assessed whether neural activation-related pial arteriolar dilation (PAD) involved interactions among adenosine (Ado) A2 receptors (A2Rs), large-conductance Ca2+-operated K+ (BKCa) channels, and inward rectifier K+ (Kir) channels. In rats with closed cranial windows, we monitored sciatic nerve stimulation (SNS)-induced PAD in the absence or presence of pharmacological blockade of A2Rs (ZM-241385), ecto-5′-nucleotidase (α,β-methylene-adenosine diphosphate), BKCa channels (paxilline), and Kir channels (BaCl2). Individually, these interventions led to 53–66% reductions in SNS-induced PADs. Combined applications of these blockers led to little or no further repression of SNS-induced PADs, suggesting interactions among A2Rs and K+ channels. In the absence of SNS, BaCl2 blockade of Kir channels produced 52–80% reductions in Ado and NS-1619 (BKCa channel activator)-induced PADs. In contrast, paxilline blockade of BKCa channels was without effect on dilations elicited by KCl (Kir channel activator) and Ado suffusions, indicating that Ado- and NS-1619-associated PADs involved Kir channels. In addition, targeted ablation of the superficial Glia limitans was associated with a selective 60–80% loss of NS-1619 responses, suggesting that the BKCa channel participation (and paxilline sensitivity) derived largely from channels within the Glia limitans. Additionally, blockade of either PKA or adenylyl cyclase caused markedly attenuated pial arteriolar responses to SNS and, in the absence of SNS, responses to Ado, KCl, and NS-1619. These findings suggested a key, possibly permissive, role for A2R-linked cAMP generation and PKA-induced K+ channel phosphorylation in somatosensory activation-evoked PAD.
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Astrocytes are a key conduit for upstream signaling of vasodilation during cerebral cortical neuronal activation in vivo.
American Journal of Physiology-Heart and Circulatory Physiology, 2008Co-Authors: Lizhen Mao, Francesco Vetri, Chanannait Paisansathan, Dale A PelligrinoAbstract:Astrocytes play an important role in the coupling between neuronal activity and brain blood flow via their capacity to "sense" neuronal activity and transmit that information to parenchymal arterioles. Here we show another role for astrocytes in neurovascular coupling: the ability to act as a signaling conduit for the vitally important process of upstream vasodilation (represented by pial arterioles) during both excessive (seizure) and physiological (sciatic nerve stimulation) increases in cerebral cortical neuronal activity. The predominance of an astrocytic rather than a vascular route was indicated by data showing that pial arteriolar-dilating responses to neuronal activation were completely blocked following selective disruption of the superficial Glia limitans, whereas interference with interendothelial signaling was without effect. Results also revealed contributions from connexin 43, implying a role for gap junctions and/or hemichannels in the signaling process and that signaling from the Glia limitans to pial arterioles may involve a diffusible mediator.
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ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation
Experimental Physiology, 2007Co-Authors: Dale A PelligrinoAbstract:Owing to their intimate anatomical relationship with cerebral arterioles, astrocytes have been postulated as signal transducers, transferring information from activated neurones to the cerebral microcirculation. These forwarded signals may involve the release of vasoactive factors from the end-feet of astrocytes. This mechanism is termed ‘neurovascular coupling’ and its anatomical components (i.e. neurone, astrocyte and vascular cells) are termed the ‘neurovascular unit’. The process of neurovascular coupling often involves upstream dilatation. This is necessary during periods of increased metabolic demand, in order to permit more blood to reach dilated downstream vessels, thereby improving nutrient supply to the activated neurones. Without it, that downstream dilatation might be ineffective, placing neurones at risk, especially during episodes of intense neuronal activity, such as seizure. In the brain, pial arterioles represent important ‘upstream’ vascular segments. The pial arterioles overlie a thick layer of astrocytic processes, termed the Glia limitans. This essentially isolates pial arterioles, anatomically, from the neurones below. Vasodilating signals that originate in the neurones therefore reach the pial arterioles via indirect pathways, primarily involving astrocytes and the Glia limitans. Here we discuss a process whereby purinergic mechanisms play a key and neuronal activity-dependent role in astrocyte to astrocyte communication, as well as in Glia limitans to pial arteriolar signals leading to vasodilatation.
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The role of the Glia limitans in ADP-induced pial arteriolar relaxation in intact and ovariectomized female rats.
American Journal of Physiology-Heart and Circulatory Physiology, 2005Co-Authors: Verna L. Baughman, Douglas L. Feinstein, Dale A PelligrinoAbstract:We examined whether the Glia limitans (GL) influences pial arteriolar relaxation elicited in vivo by the purinergic (P2Y1 receptor) agonist ADP in female rats, and whether that influence is altered...
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Influence of the Glia limitans on pial arteriolar relaxation in the rat.
American Journal of Physiology-Heart and Circulatory Physiology, 2004Co-Authors: Heidi M. Koenig, Douglas L. Feinstein, Dale A PelligrinoAbstract:We examined whether damage to the Glia limitans (GL), via exposure to the gliotoxin l-α-aminoadipic acid (l-αAAA), alters hypercapnia-induced pial arteriolar dilation in vivo. Anesthetized female r...
B. Fernández - One of the best experts on this subject based on the ideXlab platform.
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AstroGlial pattern in the spinal cord of the adult barbel (Barbus comiza).
Anatomy and Embryology, 1993Co-Authors: Guillermo Bodega, Isabel Suárez, M. Rubio, Rosa M. Villalba, B. FernándezAbstract:The distribution and the structural, ultrastructural and immunohistochemical characteristics of the astroGlial cells in the spinal cord of the adult barbel (Barbus comiza) have been studied by means of metallic impregnations (Golgi and gold-sublimate), immunohistochemical (GFAP and vimentin) and electron microscopic techniques. GFAP-positive cells were mainly distributed in the ependyma and in the periependymal region, but they have also been observed at subpial level in the anterior column. The ependymocytes were heterogeneous cells because they showed different immunohistochemical characteristics: GFAP-positive, vimentin-positive or non-immunoreactive cells. The radial astrocytes showed only GFAP immunoreactivity, and their processes ended at the subpial zone forming a continuous subpial Glia limitans. Desmosomes and gap junctions between soniata and processes of radial astrocytes were numerous, and a relationship between radial astroGlial processes and the nodes of Ranvier was also described. The perivascular Glia limitans was poorly developed and it was not complete in the blood vessels of the periependymal zone; in this case, the basal lamina was highly developed. An important characteristic in the barbel spinal cord was the existence of a zone with an abundant extracellular space near the ependyma. The presence of radial astroGlial somata at subpial level, the existence of vimentin-positive ependymocytes and the abundant extracellular space in the periependymal zone is discussed in relation to the regeneration capacity and the continuous growth showed by fish. Moreover, the abundance of gliofilaments and desmosomes leads us to suggest that mechanical support might be an important function for the astroGlial cells in the barbel spinal cord.
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Distribution and characteristics of the different astroGlial cell types in the adult lizard (Lacerta lepida) spinal cord.
Anatomy and Embryology, 1990Co-Authors: Guillermo Bodega, Isabel Suárez, M. Rubio, B. FernándezAbstract:The astroGlial cells have been studied in the lizard spinal cord by means of metallic impregnations, immunohistochemical (Glial fibrillary acidic protein) and ultrastructural methods. Three astroGlial cell types have been immunohistochemically identified: ependymocytes, radial astrocytes and astrocytes. Transitional forms have also been observed. Scarce immunopositive ependymocytes were located in the dorsal and ventral regions of the ependyma. The radial astrocytic somata were located around the ependymal layer and their processes reached the subpial Glia limitans. Typical astrocytes were the most abundant astroGlial cell type; astrocytes located in the ventral horn showed a greater development than those of the dorsal horn. In the white matter, the astrocytes were large and their processes formed part of the subpial Glia limitans; on some occasions, astrocytic cell bodies also formed part of this subpial limitans. Transitional elements between astrocytes and radial astrocytes were observed in both grey and white matter. The perivascular and subpial Glia limitans were continuous and showed a strong immunoreactivity. The comparative analysis of our results in the lizard spinal cord with those in other vertebrate groups leads us to conclude that reptiles could represent the key group in the phylogenetic evolution of the astroGlial cells in vertebrates.
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Radial astrocytes and ependymocytes in the spinal cord of the adult toad (Bufo bufo L.). An immunohistochemical and ultrastructural study.
Cell and Tissue Research, 1990Co-Authors: Guillermo Bodega, Isabel Suárez, B. FernándezAbstract:Immunohistochemical and ultrastructural techniques have been used to demonstrate Glial fibrillary acidic protein (GFAP) immuno-positive cells in the adult toad spinal cord. Two types of GFAP-immunoreactive cells were observed: ependymocytes and radial astrocytes. GFAP-positive ependymocytes were scarce and contained the immunoreactive product in their processes. They showed intermediate filaments in the basal pole and in their processes when studied with the electron microscope. These immuno-positive ependymocytes represent the tanycytic form of ependymal cells because their processes ended at the subpial zone. The radial astrocytes showed a more intensive immunoreactive product in somata and processes when they were located far away from the ependymal layer. Cell bodies and processes were also associated with blood vessels, but most of the processes ended at the subpial zone forming a continuous subpial Glia limitans. The GFAP-positive processes, which form this subpial Glia limitans in the toad spinal cord, belong to both tanycytic ependymocytes and radial astrocytes, whose somata are located in the grey matter. These findings lead us to suggest that both types of GFAP-immunopositive cells might be the functional equivalents of mammalian astrocytes.
Diana Van Driel - One of the best experts on this subject based on the ideXlab platform.
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human retinal microGlia expression of immune markers and relationship to the Glia limitans
Glia, 1995Co-Authors: Jan M Provis, Philip L Penfold, Antony J Edwards, Diana Van DrielAbstract:The immunoreactivity, morphology and relationship to the Glia limitans of microGlia were investigated in flatmounts and sections of normal human retina, using immunogold histochemistry, electron microscopy (EM), and antibodies directed against CD45, major histocompatability complex class I (MHC-I), MHC-II, and human macrophage antigens. Immunoreactivity was evident for all antibodies tested, including MHC-I, which labeled both microGlia and retinal vascular endothelium. Most consistent labeling was obtained using antibodies to CD45, MHC-II, and anti-human macrophage (S22) antigen. Immunoreactive cells were seen in the perivascular space (perivascular cells), where they were closely adherent to the vessel profile, and in the retinal parenchyma (microGlia). Some parenchymal microGlia were also vessel associated and by EM were seen to be closely related to the Glia limitans (paravascular microGlia). Paravascular microGlia were shown by optical densitometry, to express higher levels of MHC antigens than neighboring, non-vessel associated, parenchymal microGlia. In addition, paravascular microGlia were macrophage (S22) antigen positive, while other parenchymal microGlia did not express macrophage antigens. Quantitative data indicate that similar populations of microGlia are immunoreactive to CD45, MHC-I, and MHC-II, while relatively few microGlia (approximately 10%) are immunoreactive for human macrophage (S22) antigens, supporting previous suggestions that microGlia are a heterogeneous population.
Makio Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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Altered glycosylation of α-dystroglycan in neurons of Fukuyama congenital muscular dystrophy brains
Brain Research, 2006Co-Authors: Yoshiaki Saito, Tomoko Yamamoto, Makio Kobayashi, Kayoko Saito, Masashi Mizuguchi, Kousaku Ohno, Makiko OsawaAbstract:To test the hypothesis that the disruption of fukutin protein produces the brain pathology through hypoglycosylation of alpha-dystroglycan (alpha-DG), we immunostained Fukuyama congenital muscular dystrophy (FCMD) brains with an antibody that recognizes the polysaccharide epitope of alpha-DG. Immunoreactivity of the Glia-limitans along the cortical surface, as well as that of the Glial endfeet around vessel walls, was preserved in the FCMD cerebrum. However, fragmentation of the immunostained Glia-limitans was noted in association with parenchymal protrusion and gyral fusion. In the FCMD cerebellum, this fragmentation of alpha-DG labeling was limited to the area of micropolygyria, and immunostaining at the Glia-limitans and vessel walls was comparable to that of the control brains, in structurally normal areas. In the hippocampus, neurons of the dentate gyrus and corpus ammonis were immunopositive for alpha-DG in control subjects, but this staining was markedly decreased in FCMD brains. In contrast, immunolabeling of blood vessels and the Glia-limitans was preserved in this region. Fukutin antisera clearly labeled hippocampal neurons in control brains, while this labeling was decreased in FCMD brains. Thus, hypoglycosylation of alpha-DG was evident in neurons, but not in the Glial cell population of FCMD brains. This suggests that the mechanism of alpha-DG glycosylation may differ between neurons and Glial cells, and that a fukutin gene defect may result in functional disruption through hypoglycosylation of both neuronal and Glial alpha-DG.
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Expression of genes related to muscular dystrophy with lissencephaly.
Pediatric Neurology, 2004Co-Authors: Tomoko Yamamoto, Noriyuki Shibata, Yoichiro Kato, Motoko Kawaguchi, Mizuho Karita, Makio KobayashiAbstract:There is a group of congenital muscular dystrophies accompanying the brain lesions termed cobblestone lissencephaly. Abnormal Glia limitans could be considered the major pathogenesis of cobblestone lissencephaly. In this group, protein-O-linked mannose-β1,2-N-acetylglucosaminyltransferase and protein-O-mannosyltransferase 1 are considered to be responsible for muscle-eye-brain disease and Walker-Warburg syndrome, respectively, by glycosylation of α-dystroglycan. However, the functions of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, are still unclear. In this study, expression of the three aforementioned genes was compared by in situ hybridization in control cases to elucidate the functions of fukutin.Immunohistochemistry of fukutin and α-dystroglycan was also performed. In the central nervous system, all three genes were expressed in astrocytes and in immature neurons. A few mature neurons expressed fukutin, but many expressed the other two genes. All genes were expressed in various non-nervous tissues including tissues relating to secretion. Fukutin and α-dystroglycan were generally colocalized, but localization was not always the same, especially in the liver. Fukutin may be associated with the glycosylation of α-dystroglycan, and expression in astrocytes may indicate a relation to Glia limitans. The roles of fukutin in mature neurons may be less critical compared with the other two genes. Additional functions of fukutin, especially in the liver, are suspected.
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Fukutin expression in Glial cells and neurons: implication in the brain lesions of Fukuyama congenital muscular dystrophy.
Acta Neuropathologica, 2002Co-Authors: Tomoko Yamamoto, Yoichiro Kato, Makio Kobayashi, Fumiaki Muramatsu, Mizuho Karita, Hideyuki Takeiri, Kayoko Saito, Makiko OsawaAbstract:Expression and localization of fukutin, a gene responsible for Fukuyama congenital muscular dystrophy (FCMD), was studied in the central nervous system by in situ hybridization and immunohistochemistry. In control cases, Glial cells expressed fukutin and the expression continued from fetuses to adults. Double immunostaining revealed that some of these cells were astrocytes. The Glia limitans was stained by immunohistochemistry. In contrast, neuronal expression was decreased with neuronal maturation. The Glia limitans formed by endfeet of astrocytes is abnormal in the brain of fetal to adult FCMD cases. These findings suggest an important role of astrocytes for the genesis of FCMD brain, although immature neurons expressed fukutin. In FCMD cases, expression of fukutin looked decreased. In the brain of fetal FCMD cases, decreased expression of fukutin is considered to provoke the disruption of Glia limitans. In post-natal FCMD cases, prominent superficial gliosis is observed in the cerebral surface, where fukutin was weakly positive. Reactive increase of astrocytes may be required to maintain the Glia limitans for compensating the decrease of fukutin expression in individual astrocytes. In the cerebellum, Bergmann Glia, which did not express fukutin in control cases, elongated their cytoplasmic processes to the surface to form Glia limitans even in the polymicrogyric area.