The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Tatsumi Hirata - One of the best experts on this subject based on the ideXlab platform.
-
Requirement for Early-Generated Neurons Recognized by Monoclonal Antibody Lot1 in the Formation of Lateral Olfactory Tract
The Journal of Neuroscience, 2018Co-Authors: Yasufumi Sato, Tatsumi Hirata, Masaharu Ogawa, Hajime FujisawaAbstract:During development, mitral cells, the main output neurons of the Olfactory bulb, project axons into a very narrow part of the telencephalon and form an axonal bundle called the lateral Olfactory Tract (LOT). The present study shows that before the first mitral cell axons elongate, the LOT position is already marked with a subset of early-generated neurons that are recognized by monoclonal antibody lot1 (lot cells). Mitral cell axons choose the lot cell position for their growth pathway and maintain a close contact with the cells until LOT formation is completed. Ablation of lot cells prevented LOT formation in organotypic culture. These results suggest that lot cells are 'guidepost cells' for mitral cell axons.
-
guidepost neurons for the lateral Olfactory Tract expression of metabotropic glutamate receptor 1 and innervation by glutamatergic Olfactory bulb axons
Developmental Neurobiology, 2012Co-Authors: Tatsumi Hirata, Takahiko Kawasaki, Atsu Aiba, Tatsuro Kumada, Tomonori Furukawa, Francois Conquet, Yumiko Saga, Atsuo FukudaAbstract:The guidepost neurons for the lateral Olfactory Tract, which are called lot cells, are the earliest-generated neurons in the neocortex. They migrate tangentially and ventrally further down this Tract, and provide scaffolding for the Olfactory bulb axons projecting into this pathway. The molecular profiles of the lot cells are largely uncharacterized. We found that lot cells specifically express metabotropic glutamate receptor subtype-1 at a very early stage of development. This receptor is functionally competent and responds to a metabotropic glutamate receptor agonist with a transient increase in the intracellular calcium ion concentration. When the glutamatergic Olfactory bulb axons were electrically stimulated, lot cells responded to the stimulation with a calcium increase mainly via ionotropic glutamate receptors, suggesting potential neurotransmission between the axons and lot cells during early development. Together with the finding that lot cells themselves are glutamatergic excitatory neurons, our results provide another notable example of precocious interactions between the projecting axons and their intermediate targets.
-
Semaphorin 3F Confines Ventral Tangential Migration of Lateral Olfactory Tract Neurons onto the Telencephalon Surface
The Journal of Neuroscience, 2008Co-Authors: Takahiko Kawasaki, Seiji Takashima, Ikuo Matsuda, Atsu Aiba, Tatsumi HirataAbstract:Ventral tangential migration of neurons is the most prominent mode of neuronal translocation during earliest neurogenesis in the mouse telencephalon. A typical example of the neurons that adopt this migration mode is guidepost neurons in the lateral Olfactory Tract designated as lot cells. These neurons are generated from the neocortical neuroepithelium and migrate tangentially down to the ventral edge of the neocortex abutting the ganglionic eminence, on which the future lateral Olfactory Tract develops. We show here that this migration stream is repelled by a secreted axon guidance molecule, semaphorin 3F through interaction with its specific receptor, neuropilin-2. Accordingly, in mutant mice for semaphorin 3F or neuropilin-2, lot cells ectopically penetrated into the deep brain domain, which normally expresses semaphorin 3F. These results reveal that semaphorin 3F is an important regulator of the ventral tangential migration stream, confining the migrating neurons on the telencephalon surface by repelling from the deeper domain.
-
Robo1 and robo2 control the development of the lateral Olfactory Tract.
Journal of Neuroscience, 2007Co-Authors: Coralie Fouquet, Tatsumi Hirata, Alain Chédotal, Thomas Di Meglio, Takahiko Kawasaki, Hua Long, Marc Tessier-lavigne, Kim T Nguyen-ba-charvetAbstract:The development of Olfactory bulb projections that form the lateral Olfactory Tract (LOT) is still poorly understood. It is known that the septum secretes Slit1 and Slit2 which repel Olfactory axons in vitro and that in Slit1-/-;Slit2-/- mutant mice, the LOT is profoundly disrupted. However, the involvement of Slit receptors, the roundabout (Robo) proteins, in guiding LOT axons has not been demonstrated. We show here that both Robo1 and Robo2 receptors are expressed on early developing LOT axons, but that only Robo2 is present at later developmental stages. Olfactory bulb axons from Robo1-/-;Robo2-/- double-mutant mice are not repelled by Slit in vitro. The LOT develops normally in Robo1-/- mice, but is completely disorganized in Robo2-/- and Robo1-/-;Robo2-/- double-mutant embryos, with many LOT axons spreading along the ventral surface of the telencephalon. Finally, the position of lot1-expressing cells, which have been proposed to be the LOT guidepost cells, appears unaffected in Slit1-/-;Slit2-/- mice and in Robo1-/-;Robo2-/- mice. Together, our results indicate that Robo1 and Robo2 directly mediate the repulsive activity of Slit receptors on LOT axons, and are required for normal guidance of these axons in vivo.
-
netrin 1 regulates ventral tangential migration of guidepost neurons in the lateral Olfactory Tract
Development, 2006Co-Authors: Takahiko Kawasaki, Keisuke Ito, Tatsumi HirataAbstract:In the developing nervous system, functional neural networks are constructed with intricate coordination of neuronal migrations and axonal projections. We have previously reported a ventral tangential migration of a special type of cortical neurons, lot cells, in the mouse embryo. These neurons originate from the ventricular zone of the entire neocortex, tangentially migrate in the surface layer of the neocortex into the ventral direction, align in the future pathway of the lateral Olfactory Tract (LOT) and eventually guide the projection of LOT axons. In this study, we developed an organotypic culture system to investigate the regulation of this cell migration in the developing telencephalon. Our data show that the neocortex contains the signals that direct lot cells ventrally, that the ganglionic eminence excludes lot cells by repelling the migration and that lot cells are atTracted to netrin 1, an axon guidance factor. Furthermore, we demonstrate that mutations in the genes encoding netrin 1 and its functional receptor Dcc lead to inappropriate distribution of lot cells and subsequent partial disruption of LOT projection. These results suggest that netrin 1 regulates the migration of lot cells and LOT projections, possibly by ensuring the correct distribution of these guidepost neurons.
Keita Takahashi - One of the best experts on this subject based on the ideXlab platform.
-
cerebrospinal fluid level of nogo receptor 1 antagonist lateral Olfactory Tract usher substance lotus correlates inversely with the extent of neuroinflammation
Journal of Neuroinflammation, 2018Co-Authors: Keita Takahashi, Hideyuki Takeuchi, Yuji Kurihara, Hiroshi Doi, Misako Kunii, Kenichi Tanaka, Haruko Nakamura, Ryoko Fukai, Atsuko Tomitakatsumoto, Mikiko TadaAbstract:Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral Olfactory Tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.
-
Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral Olfactory Tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation
BMC, 2018Co-Authors: Keita Takahashi, Hideyuki Takeuchi, Yuji Kurihara, Hiroshi Doi, Misako Kunii, Kenichi Tanaka, Haruko Nakamura, Ryoko Fukai, Atsuko Tomita-katsumoto, Mikiko TadaAbstract:AbsTract Background Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral Olfactory Tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. Methods CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. Results Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. Conclusions CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases
-
association of multiple sclerosis with lateral Olfactory Tract usher substance lotus a possible endogenous inhibitor of axonal degeneration
Clinical and Experimental Neuroimmunology, 2015Co-Authors: Keita Takahashi, Kohtaro Takei, Fumiaki TanakaAbstract:Neuronal regeneration in the adult mammalian central nervous system (CNS) is restricted after brain injury, and some of myelin components and their common receptor, Nogo receptor-1 (NgR1), have been identified as the key molecules for limiting axonal regeneration in the CNS. They have been widely studied as therapeutic targets to overcome the limitation of neuronal regeneration, and strategies using antagonism to NgR1 are expected for the development of the most promising therapies. Recently signaling through NgR1 was shown to be an underlying mechanism of axonal degeneration in multiple sclerosis (MS). Although MS is generally considered an autoimmune demyelinating disorder, axonal degeneration has recently atTracted attention as an important pathological feature and one of the mechanisms leading to progressive neurological disability. These pathological and clinical features of MS suggest that molecules involved in limitation of axonal growth can be potential candidates for MS biomarker and therapeutic target, and recent studies have supported these hypotheses. We have previously identified a novel endogenous NgR1 antagonist and named it lateral Olfactory Tract usher substance (LOTUS). Our data showed that LOTUS promotes axonal growth through blocking of NgR1 signaling, suggesting that LOTUS could be an endogenous inhibitor of axonal degeneration. Furthermore, our recent study demonstrated an interesting variation of LOTUS level in the cerebrospinal fluid of MS patients that was well correlated with disease activity. Here, we review the association of MS with the molecules related to axonal growth including LOTUS, and discuss the clinical application of LOTUS as a promising biomarker and therapeutic target.
-
association of cerebrospinal fluid levels of lateral Olfactory Tract usher substance lotus with disease activity in multiple sclerosis
JAMA Neurology, 2015Co-Authors: Keita Takahashi, Yuji Kurihara, Yoshio Goshima, Fumiaki Tanaka, Yume Suzuki, Kohtaro TakeiAbstract:Importance Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral Olfactory Tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. Objective To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. Design, Setting, and Participants Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. Main Outcomes and Measures The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. Results The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] µg/dL) was lower than that of NCs (19.2 [4.7] µg/dL; P P Conclusions and Relevance Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.
Kohtaro Takei - One of the best experts on this subject based on the ideXlab platform.
-
axonal branching in lateral Olfactory Tract is promoted by nogo signaling
Scientific Reports, 2016Co-Authors: Masumi Iketani, Yuji Kurihara, Takaakira Yokoyama, Stephen M Strittmatter, Yoshio Goshima, Nobutaka Kawahara, Kohtaro TakeiAbstract:Mitral cells are major projection neurons of the Olfactory bulb (OB) that form an axonal bundle known as the lateral Olfactory Tract (LOT). After axonal bundle formation, collateral branches sprout from primary axons of the LOT. Recently, we identified LOT usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist and demonstrated that LOTUS contributes to the formation of the LOT axonal bundle. Immunoblots revealed that the expression level of Nogo-A in the OB developmentally increased during axonal collateral formation. Next, we found that the axonal collateral branches were increased in cultured OB neurons from LOTUS-knockout (KO) mice, whereas they were decreased in cultured OB neurons from NgR1-KO mice. Knockdown of Nogo-A in cultured OB neurons reduced the number of axonal collateral branches, suggesting that endogenous Nogo-A induces axonal branching. Finally, the collateral branches of the LOT were increased in LOTUS-KO mice, whereas those in NgR1-KO mice were decreased. Moreover, the abnormal increase of axonal branching observed in LOTUS-KO mice was rescued in the double mutant of LOTUS- and NgR1-KO mice. These findings suggest that Nogo-A and NgR1 interactions may contribute to axonal branching in LOT development.
-
association of multiple sclerosis with lateral Olfactory Tract usher substance lotus a possible endogenous inhibitor of axonal degeneration
Clinical and Experimental Neuroimmunology, 2015Co-Authors: Keita Takahashi, Kohtaro Takei, Fumiaki TanakaAbstract:Neuronal regeneration in the adult mammalian central nervous system (CNS) is restricted after brain injury, and some of myelin components and their common receptor, Nogo receptor-1 (NgR1), have been identified as the key molecules for limiting axonal regeneration in the CNS. They have been widely studied as therapeutic targets to overcome the limitation of neuronal regeneration, and strategies using antagonism to NgR1 are expected for the development of the most promising therapies. Recently signaling through NgR1 was shown to be an underlying mechanism of axonal degeneration in multiple sclerosis (MS). Although MS is generally considered an autoimmune demyelinating disorder, axonal degeneration has recently atTracted attention as an important pathological feature and one of the mechanisms leading to progressive neurological disability. These pathological and clinical features of MS suggest that molecules involved in limitation of axonal growth can be potential candidates for MS biomarker and therapeutic target, and recent studies have supported these hypotheses. We have previously identified a novel endogenous NgR1 antagonist and named it lateral Olfactory Tract usher substance (LOTUS). Our data showed that LOTUS promotes axonal growth through blocking of NgR1 signaling, suggesting that LOTUS could be an endogenous inhibitor of axonal degeneration. Furthermore, our recent study demonstrated an interesting variation of LOTUS level in the cerebrospinal fluid of MS patients that was well correlated with disease activity. Here, we review the association of MS with the molecules related to axonal growth including LOTUS, and discuss the clinical application of LOTUS as a promising biomarker and therapeutic target.
-
association of cerebrospinal fluid levels of lateral Olfactory Tract usher substance lotus with disease activity in multiple sclerosis
JAMA Neurology, 2015Co-Authors: Keita Takahashi, Yuji Kurihara, Yoshio Goshima, Fumiaki Tanaka, Yume Suzuki, Kohtaro TakeiAbstract:Importance Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral Olfactory Tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. Objective To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. Design, Setting, and Participants Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. Main Outcomes and Measures The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. Results The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] µg/dL) was lower than that of NCs (19.2 [4.7] µg/dL; P P Conclusions and Relevance Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.
Yuji Kurihara - One of the best experts on this subject based on the ideXlab platform.
-
cerebrospinal fluid level of nogo receptor 1 antagonist lateral Olfactory Tract usher substance lotus correlates inversely with the extent of neuroinflammation
Journal of Neuroinflammation, 2018Co-Authors: Keita Takahashi, Hideyuki Takeuchi, Yuji Kurihara, Hiroshi Doi, Misako Kunii, Kenichi Tanaka, Haruko Nakamura, Ryoko Fukai, Atsuko Tomitakatsumoto, Mikiko TadaAbstract:Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral Olfactory Tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.
-
Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral Olfactory Tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation
BMC, 2018Co-Authors: Keita Takahashi, Hideyuki Takeuchi, Yuji Kurihara, Hiroshi Doi, Misako Kunii, Kenichi Tanaka, Haruko Nakamura, Ryoko Fukai, Atsuko Tomita-katsumoto, Mikiko TadaAbstract:AbsTract Background Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral Olfactory Tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. Methods CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. Results Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. Conclusions CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases
-
axonal branching in lateral Olfactory Tract is promoted by nogo signaling
Scientific Reports, 2016Co-Authors: Masumi Iketani, Yuji Kurihara, Takaakira Yokoyama, Stephen M Strittmatter, Yoshio Goshima, Nobutaka Kawahara, Kohtaro TakeiAbstract:Mitral cells are major projection neurons of the Olfactory bulb (OB) that form an axonal bundle known as the lateral Olfactory Tract (LOT). After axonal bundle formation, collateral branches sprout from primary axons of the LOT. Recently, we identified LOT usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist and demonstrated that LOTUS contributes to the formation of the LOT axonal bundle. Immunoblots revealed that the expression level of Nogo-A in the OB developmentally increased during axonal collateral formation. Next, we found that the axonal collateral branches were increased in cultured OB neurons from LOTUS-knockout (KO) mice, whereas they were decreased in cultured OB neurons from NgR1-KO mice. Knockdown of Nogo-A in cultured OB neurons reduced the number of axonal collateral branches, suggesting that endogenous Nogo-A induces axonal branching. Finally, the collateral branches of the LOT were increased in LOTUS-KO mice, whereas those in NgR1-KO mice were decreased. Moreover, the abnormal increase of axonal branching observed in LOTUS-KO mice was rescued in the double mutant of LOTUS- and NgR1-KO mice. These findings suggest that Nogo-A and NgR1 interactions may contribute to axonal branching in LOT development.
-
association of cerebrospinal fluid levels of lateral Olfactory Tract usher substance lotus with disease activity in multiple sclerosis
JAMA Neurology, 2015Co-Authors: Keita Takahashi, Yuji Kurihara, Yoshio Goshima, Fumiaki Tanaka, Yume Suzuki, Kohtaro TakeiAbstract:Importance Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral Olfactory Tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. Objective To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. Design, Setting, and Participants Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. Main Outcomes and Measures The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. Results The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] µg/dL) was lower than that of NCs (19.2 [4.7] µg/dL; P P Conclusions and Relevance Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.
Takahiko Kawasaki - One of the best experts on this subject based on the ideXlab platform.
-
guidepost neurons for the lateral Olfactory Tract expression of metabotropic glutamate receptor 1 and innervation by glutamatergic Olfactory bulb axons
Developmental Neurobiology, 2012Co-Authors: Tatsumi Hirata, Takahiko Kawasaki, Atsu Aiba, Tatsuro Kumada, Tomonori Furukawa, Francois Conquet, Yumiko Saga, Atsuo FukudaAbstract:The guidepost neurons for the lateral Olfactory Tract, which are called lot cells, are the earliest-generated neurons in the neocortex. They migrate tangentially and ventrally further down this Tract, and provide scaffolding for the Olfactory bulb axons projecting into this pathway. The molecular profiles of the lot cells are largely uncharacterized. We found that lot cells specifically express metabotropic glutamate receptor subtype-1 at a very early stage of development. This receptor is functionally competent and responds to a metabotropic glutamate receptor agonist with a transient increase in the intracellular calcium ion concentration. When the glutamatergic Olfactory bulb axons were electrically stimulated, lot cells responded to the stimulation with a calcium increase mainly via ionotropic glutamate receptors, suggesting potential neurotransmission between the axons and lot cells during early development. Together with the finding that lot cells themselves are glutamatergic excitatory neurons, our results provide another notable example of precocious interactions between the projecting axons and their intermediate targets.
-
Semaphorin 3F Confines Ventral Tangential Migration of Lateral Olfactory Tract Neurons onto the Telencephalon Surface
The Journal of Neuroscience, 2008Co-Authors: Takahiko Kawasaki, Seiji Takashima, Ikuo Matsuda, Atsu Aiba, Tatsumi HirataAbstract:Ventral tangential migration of neurons is the most prominent mode of neuronal translocation during earliest neurogenesis in the mouse telencephalon. A typical example of the neurons that adopt this migration mode is guidepost neurons in the lateral Olfactory Tract designated as lot cells. These neurons are generated from the neocortical neuroepithelium and migrate tangentially down to the ventral edge of the neocortex abutting the ganglionic eminence, on which the future lateral Olfactory Tract develops. We show here that this migration stream is repelled by a secreted axon guidance molecule, semaphorin 3F through interaction with its specific receptor, neuropilin-2. Accordingly, in mutant mice for semaphorin 3F or neuropilin-2, lot cells ectopically penetrated into the deep brain domain, which normally expresses semaphorin 3F. These results reveal that semaphorin 3F is an important regulator of the ventral tangential migration stream, confining the migrating neurons on the telencephalon surface by repelling from the deeper domain.
-
Robo1 and robo2 control the development of the lateral Olfactory Tract.
Journal of Neuroscience, 2007Co-Authors: Coralie Fouquet, Tatsumi Hirata, Alain Chédotal, Thomas Di Meglio, Takahiko Kawasaki, Hua Long, Marc Tessier-lavigne, Kim T Nguyen-ba-charvetAbstract:The development of Olfactory bulb projections that form the lateral Olfactory Tract (LOT) is still poorly understood. It is known that the septum secretes Slit1 and Slit2 which repel Olfactory axons in vitro and that in Slit1-/-;Slit2-/- mutant mice, the LOT is profoundly disrupted. However, the involvement of Slit receptors, the roundabout (Robo) proteins, in guiding LOT axons has not been demonstrated. We show here that both Robo1 and Robo2 receptors are expressed on early developing LOT axons, but that only Robo2 is present at later developmental stages. Olfactory bulb axons from Robo1-/-;Robo2-/- double-mutant mice are not repelled by Slit in vitro. The LOT develops normally in Robo1-/- mice, but is completely disorganized in Robo2-/- and Robo1-/-;Robo2-/- double-mutant embryos, with many LOT axons spreading along the ventral surface of the telencephalon. Finally, the position of lot1-expressing cells, which have been proposed to be the LOT guidepost cells, appears unaffected in Slit1-/-;Slit2-/- mice and in Robo1-/-;Robo2-/- mice. Together, our results indicate that Robo1 and Robo2 directly mediate the repulsive activity of Slit receptors on LOT axons, and are required for normal guidance of these axons in vivo.
-
netrin 1 regulates ventral tangential migration of guidepost neurons in the lateral Olfactory Tract
Development, 2006Co-Authors: Takahiko Kawasaki, Keisuke Ito, Tatsumi HirataAbstract:In the developing nervous system, functional neural networks are constructed with intricate coordination of neuronal migrations and axonal projections. We have previously reported a ventral tangential migration of a special type of cortical neurons, lot cells, in the mouse embryo. These neurons originate from the ventricular zone of the entire neocortex, tangentially migrate in the surface layer of the neocortex into the ventral direction, align in the future pathway of the lateral Olfactory Tract (LOT) and eventually guide the projection of LOT axons. In this study, we developed an organotypic culture system to investigate the regulation of this cell migration in the developing telencephalon. Our data show that the neocortex contains the signals that direct lot cells ventrally, that the ganglionic eminence excludes lot cells by repelling the migration and that lot cells are atTracted to netrin 1, an axon guidance factor. Furthermore, we demonstrate that mutations in the genes encoding netrin 1 and its functional receptor Dcc lead to inappropriate distribution of lot cells and subsequent partial disruption of LOT projection. These results suggest that netrin 1 regulates the migration of lot cells and LOT projections, possibly by ensuring the correct distribution of these guidepost neurons.
-
systematic screening and identification of antigens recognized by monoclonal antibodies raised against the developing lateral Olfactory Tract
Journal of Neurobiology, 2005Co-Authors: Takahiko Kawasaki, Yoshiko Takagi, Hitoshi Yamatani, Tatsumi HirataAbstract:During development, Olfactory bulb axons navigate a complex microenvironment composed of myriad molecules to construct a bundle called the lateral Olfactory Tract. The axons themselves also express thousands of different molecules. In the present study, we produced and characterized six monoclonal antibodies that label the lateral Olfactory Tract and its surroundings in a unique pattern. The labeling profiles suggested that the antigen molecules recognized by each antibody are heterogeneously distributed around the developing lateral Olfactory Tract. We developed an efficient screening method to identify the antigen molecules by combining expression of a cDNA library in COS-7 cells and the subsequent immunohistochemical staining of the cells. The systematic screening successfully identified specific cDNA clones for all of the monoclonal antibodies, which highly probably coded for the antigen molecules, and therefore unveiled the molecular nature of local components that embrace the developing lateral Olfactory Tract in mice.
