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Toshihide Yamashita - One of the best experts on this subject based on the ideXlab platform.
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Repulsive Guidance Molecule A Regulates Adult Neurogenesis Via the Neogenin Receptor.
Neuroscience insights, 2020Co-Authors: Toke Jost Isaksen, Toshihide YamashitaAbstract:Repulsive Guidance Molecule A (RGMa) exhibits Repulsive Guidance of axonal growth and regulates neuronal differentiation during development of the mammalian brain. In this commentary, we describe the findings of our recent paper, "Repulsive Guidance Molecule A Suppresses Adult Neurogenesis," and discuss a possible model for RGMa suppression of newborn neurons that fail to properly migrate into the granular cell layer. In the study, we provided evidence that RGMa suppressed neurite growth and survival of newborn neurons in the adult dentate gyrus. This effect depends on the multifunctional Neogenin receptor expressed in adult neural stem cells through activation of the Rho-associated protein kinase leading to neurite growth inhibition and ultimately cell death. It should be noted that both RGMa and Neogenin interact with several well-described Molecules, including bone morphogenetic proteins, that regulate neuronal development. Thus, it is likely that RGMa interacts with other intricate molecular networks that regulate adult neurogenesis.
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Repulsive Guidance Molecule A Suppresses Adult Neurogenesis.
Stem cell reports, 2020Co-Authors: Toke Jost Isaksen, Yuki Fujita, Toshihide YamashitaAbstract:Summary Repulsive Guidance Molecule A (RGMa) is a glycosylphosphatidylinositol-anchored glycoprotein that exhibits Repulsive neurite Guidance and regulates neuronal differentiation and survival during brain development. However, the function of RGMa in the adult brain is unknown. Here, we show that RGMa is expressed in the adult hippocampus and provide evidence that RGMa signaling suppresses adult neurogenesis. Knockdown of RGMa in the dentate gyrus increased the number of surviving newborn neurons; however, these cells failed to properly migrate into the granular cell layer. In vitro, RGMa stimulation of adult neural stem cells suppressed neurite outgrowth of newborn neurons, which could be prevented by knockdown of the multifunctional receptor neogenin, as well as pharmacological inhibition of the downstream target Rho-associated protein kinase. These findings present a function for RGMa in the adult brain and add to the intricate molecular network that regulates adult brain plasticity.
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Anti-Repulsive Guidance Molecule-a antibody treatment and repetitive transcranial magnetic stimulation have synergistic effects on motor recovery after spinal cord injury.
Neuroscience letters, 2019Co-Authors: Toru Nakanishi, Yuki Fujita, Takashi Tanaka, Toshihide YamashitaAbstract:Damaged axons in the adult central nervous system (CNS) fail to regenerate spontaneously due to several intrinsic and extrinsic factors that inhibit axon elongation. An extrinsic inhibitory factor, Repulsive Guidance Molecule-a (RGMa), is upregulated around spinal cord lesion sites. Inhibition of RGMa using an antibody promotes axon sprouting, regeneration, and motor recovery after spinal cord injury (SCI) in rodents and primates. Repetitive transcranial magnetic stimulation (rTMS) has been used as a form of rehabilitation, and accumulating studies have suggested that rTMS is able to modulate neural plasticity of the cortex. Here, we conducted rTMS with anti-RGMa antibody treatment in mice with SCI to investigate the potential synergistic effects on motor recovery. Although mice treated with anti-RGMa antibody and rTMS concomitantly did not show significant motor recovery, mice treated sequentially with anti-RGMa antibody followed by rTMS showed better motor performance than mice treated with anti-RGMa antibody alone. Moreover, we found that Ca2+/calmodulin-dependent kinase II (CaMKII) was upregulated in mice treated with anti-RGMa antibody and rTMS sequentially compared with mice received a single anti-RGMa antibody treatment. These results suggest that anti-RGMa antibody treatment and rTMS intervention have synergistic effects on motor recovery, and that the timing of rTMS intervention is a critical factor to maximize the effect of anti-RGMa antibody treatment. These interventions may provide new therapeutic strategies for promoting motor recovery after SCI.
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Inhibiting Repulsive Guidance Molecule-a suppresses secondary progression in mouse models of multiple sclerosis
Cell death & disease, 2018Co-Authors: Shogo Tanabe, Yuki Fujita, Kaori Ikuma, Toshihide YamashitaAbstract:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is characterized by motor deficits, fatigue, pain, cognitive impairment, and sensory and visual dysfunction. Secondary progressive multiple sclerosis (SPMS) is a progressive form of MS that develops from relapsing-remitting MS. Repulsive Guidance Molecule-a (RGMa) has diverse functions, including axon growth inhibition and immune regulation. Here, we show inhibiting RGMa had therapeutic effects in mouse models of SPMS. We induced experimental autoimmune encephalomyelitis in nonobese diabetic mice (NOD-EAE mice) and treated them with humanized anti-RGMa monoclonal antibody. This treatment significantly suppressed secondary progression of disease and inflammation, demyelination and axonal degeneration. In addition, treatment with anti-RGMa antibody promoted the growth of corticospinal tracts and motor recovery in targeted EAE mice with inflammatory lesions in the spinal cord. Collectively, these results show that a humanized anti-RGMa antibody has therapeutic effects in mouse models of SPMS.
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Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury
Cerebral cortex (New York N.Y. : 1991), 2018Co-Authors: Hiroshi Nakagawa, Toshihide Yamashita, Taihei Ninomiya, Masahiko TakadaAbstract:Axons in the mature mammalian central nervous system have only a limited capacity to grow/regenerate after injury, and spontaneous recovery of motor functions is therefore not greatly expected in spinal cord injury (SCI). To promote functional recovery after SCI, it is critical that corticospinal tract (CST) fibers reconnect properly with target spinal neurons through enhanced axonal growth/regeneration. Here, we applied antibody treatment against Repulsive Guidance Molecule-a (RGMa) to a monkey model of SCI. We found that inhibition of upregulated RGMa around the lesioned site in the cervical cord resulted in recovery from impaired manual dexterity by accentuated penetration of CST fibers into laminae VII and IX, where spinal interneurons and motoneurons are located, respectively. Furthermore, pharmacological inactivation following intracortical microstimulation revealed that the contralesional, but not the ipsilesional, primary motor cortex was crucially involved in functional recovery at a late stage in our SCI model. The present data indicate that treatment with the neutralizing antibody against RGMa after SCI is a potential target for achieving restored manual dexterity in primates.
Yin Xia - One of the best experts on this subject based on the ideXlab platform.
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Repulsive Guidance Molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway.
Cellular signalling, 2016Co-Authors: Jiangfeng Liu, Yin Xia, Herbert Y. Lin, Weiling Wang, Ming Liu, Hong Zhou, Jianhua Ran, Baoxue YangAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive Guidance Molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD.
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Repulsive Guidance Molecule b (RGMb) Is Dispensable for Normal Gonadal Function in Mice
Biology of reproduction, 2016Co-Authors: Chenling Meng, Alan L Schneyer, Wenjing Liu, Huihui Huang, Yang Wang, Binbin Chen, Gordon J. Freeman, Herbert Y. Lin, Yin XiaAbstract:Bone morphogenetic protein (BMP) signaling plays an important role in spermatogenesis and follicle development. Our previous studies have shown that Repulsive Guidance Molecule b (RGMb, also known as Dragon) is a coreceptor that enhances BMP2 and BMP4 signaling in several cell types and that RGMb is expressed in spermatocytes and spermatids in the testis and in oocytes of the secondary follicles in the ovary. Here, we demonstrated that specific deletion of Rgmb in germ cells in the testis and ovary did not alter Smad1/5/8 phosphorylation, gonadal structures, and fertility. In addition, ovaries from postnatal global Rgmb knockout mice showed similar structures to the wild-type ovaries. Our results suggest that RGMb is not essential for normal gonadal function.
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Dragon (Repulsive Guidance Molecule b, RGMb) is a novel gene that promotes colorectal cancer growth
Oncotarget, 2015Co-Authors: Ying Shi, Yin Xia, Guo-bin Chen, Xiaoxiao Huang, Chuan-xing Xiao, Huan-huan Wang, Jinfang Zhang, Jian-lin RenAbstract:// Ying Shi 1 , Guo-Bin Chen 1 , Xiao-Xiao Huang 1 , Chuan-Xing Xiao 1 , Huan-Huan Wang 1 , Ye-Sen Li 6,7 , Jin-Fang Zhang 4 , Shao Li 8 , Yin Xia 4,5 , Jian-Lin Ren 1 and Bayasi Guleng 1,2,3 1 Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China 2 Faculty of Clinical Medicine, Medical College, Xiamen University, Xiamen, Fujian Province, China 3 State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian Province, China 4 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China 5 School of Biomedical Sciences Core Laboratory, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China 6 Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, China 7 Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian Province, China 8 MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China Correspondence to: Bayasi Guleng, email: // Jian-Lin Ren, email: // Yin Xia, email: // Keywords: dragon, colorectal cancer, BMP, Smad1/5/8, Erk1/2, proliferation Received : January 11, 2015 Accepted : April 21, 2015 Published : May 12, 2015 Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer death. However, the molecular mechanisms underlying CRC initiation, growth and metastasis are poorly understood. Dragon (RGMb), a member of the Repulsive Guidance Molecule (RGM) family, has been recently identified as a co-receptor for bone morphogenetic protein (BMP) signaling, but the role of Dragon in CRC development is undefined. Here, we show that Dragon expression was increased in colon cancer tissues compared to control tissues in CAC mouse model and in human patients. Dragon promoted proliferation of CT26.WT and CMT93 colon cancer cells and accelerated tumor growth in the xenograft mouse model. Dragon’s action on colon cancer development was mediated via the BMP4-Smad1/5/8 and Erk1/2 pathways. Therefore, our results have revealed that Dragon is a novel gene that promotes CRC growth through the BMP pathway. Dragon may be exploited as a potential therapeutic target for CRC treatment.
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expression of Repulsive Guidance Molecule b rgmb in the uterus and ovary during the estrous cycle in rats
Acta Histochemica, 2014Co-Authors: Chenling Meng, Yin Xia, Alan L Schneyer, Nannan Guo, Quanwei Wei, Fangxiong Shi, Dagan MaoAbstract:Repulsive Guidance Molecule b (RGMb; a.k.a. Dragon), initially identified in the embryonic dorsal root ganglion, is the first member of the RGM family shown to enhance bone morphogenetic protein (BMP) signaling by acting as a BMP co-receptor. BMP signaling has been demonstrated to play an important role in the reproductive organs. Our previous study found that RGMb was expressed in the reproductive axis, but whether RGMb expression in reproductive organs changes across the estrous cycle remains unknown. Here, we show in the rat that RGMb mRNA expression in the uterus was significantly higher during metesterus and diestrus than during proestrus and estrus. Western blotting indicated that RGMb protein was significantly lower during estrus compared with the other three stages. Immunohistochemistry revealed that RGMb protein was mainly localized to the uterine luminal and glandular epithelial cells of the endometrium. RGMb mRNA and protein in the ovary remained unchanged during the estrous cycle. RGMb protein was expressed in the oocytes of all follicles. Weak staining for RGMb protein was also found in corpora lutea. RGMb was not detected in granulosa cells and stromal cells. Taken together, RGMb expression in the uterus and ovary across the estrus cycle demonstrate that RGMb may be involved in the regulation of uterine function, follicular development as well as luteal activity.
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dragon Repulsive Guidance Molecule rgmb inhibits e cadherin expression and induces apoptosis in renal tubular epithelial cells
Journal of Biological Chemistry, 2013Co-Authors: Wenjing Liu, Herbert Y. Lin, Baoxue Yang, Yueshui Zhao, Xiao-ming Meng, Chao Wan, Hui Y. Lan, Yin XiaAbstract:Dragon is one of the three members of the Repulsive Guidance Molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-β in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45–66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo. Background: Dragon is expressed in kidney tubular epithelial cells. Results: Dragon inhibits E-cadherin expression and induces apoptosis in IMCD3 cells, and Dragon+/− mice exhibit increased E-cadherin expression and decreased apoptosis in injured renal tubules. Conclusion: Dragon inhibits E-cadherin and induces apoptosis in renal tubular cells both in vitro and in vivo. Significance: Our results provide a novel mechanism underlying kidney injury.
Xinyue Qin - One of the best experts on this subject based on the ideXlab platform.
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Elevated Repulsive Guidance Molecule-a mRNA in peripheral blood mononuclear cells are associated with impaired leptomeningeal collaterals in patients with middle cerebral artery occlusions
Annals of palliative medicine, 2020Co-Authors: Beibei Gong, Jun Yang, Xinyue QinAbstract:Background In the event of middle cerebral artery occlusion (MCAO), leptomeningeal collaterals (LMCs) play a crucial role in determining the survival of brain tissue distal to occlusion. Previous findings indicated that genes controlling arteriogenesis can impact the extent of LMCs. Therefore, probe for potential genetic parameters correlating of arteriogenesis may be clinically useful in predicting LMCs status in MCAO. During the screening process, we focused on Repulsive Guidance Molecule a (RGMa), which has been reported to play a negative role in angiogenesis after stroke by decreasing the proliferation, migration, and tube formation of endothelial cells (ECs) in vivo and in vitro. Indeed, endothelial function plays a main role in arteriogenesis and is essential in determining the LMCs status. Therefore, in present study, we aimed to testify the hypothesis that RGMa might be associated with LMCs status in MCAO. Methods We prospectively enrolled patients with acute M1 MCA +/- intracranial internal carotid artery (ICA) occlusions (n=96) and healthy controls (n=33). Status of LMCs was evaluated according to computed tomographic angiography (CTA) on admission. Baseline RGMa mRNA expression was quantified by using quantitative real-time PCR. Results Patients with poor LMCs showed significantly higher RGMa mRNA levels than patients with good LMCs status (P=0.001) as well as healthy controls (P=0.002), respectively; whereas good LMCs group showed similar baseline RGMa levels than controls (P=1.000). RGMa mRNA level and baseline NIHSS score were independent predictors for impaired LMCs. Conclusions In MCAO patients, elevated PBMCs RGMa mRNA levels were associated with impaired LMCs status, indicating that measurement of RGMa mRNA expression in the early phase of stroke, together with other clinical approaches, was logically expected to be useful for predicting LMCs status. Moreover, a role for RGMa in leptomeningeal arteriogenesis following ischemic stroke can be hypothesized.
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Repulsive Guidance Molecule a suppresses angiogenesis after ischemia reperfusion injury of middle cerebral artery occlusion in rats
Neuroscience Letters, 2018Co-Authors: Yu Wang, Gang Zhang, Rongrong Zhang, Xiangfeng Xing, Jia Guo, Fei Xie, Xinyue QinAbstract:Repulsive Guidance Molecule a (RGMa) has now emerged as a Molecule with pleiotropic roles, including repulsion, adhesion, migration and differentiation in the nervous system. In this study, adult male Sprague-Dawley (SD) rats received 90-min middle cerebral artery occlusion (MCAO) to observe RGMa/neogenin expression sites after ischemia/reperfusion injury and changes in angiogenesis after treatment with RNA interference using RGMa-specific recombinant adenovirus rAd5-shRNA-RGMa (rAd-shRGMa). To clarify how RGMa mediates angiogenesis, the RGMa function-blocking peptide six fibronectin type III (6FNIII) was also administered, and corresponding changes in vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang2), angiopoietin-1 (Ang1), and brain derived neurotrophic factor (BDNF) were determined by western blotting. Both RGMa and its receptor neogenin were expressed in neurons and vessel endothelial cells after ischemia/reperfusion injury, and angiogenesis, coupled with functional recovery, was enhanced after RNA interference against RGMa compared with the vehicle groups. VEGF, Ang2, Ang1 and BDNF expression levels were significantly increased after intervention with rAd-shRGMa or 6FNIII. Thus, RGMa might suppress angiogenesis via VEGF, Ang2, Ang1 and BDNF after cerebral ischemia/reperfusion injury, which has therapeutic potential by reducing these endogenous detrimental mechanisms.
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Repulsive Guidance Molecule a suppresses angiogenesis after ischemia/reperfusion injury of middle cerebral artery occlusion in rats
Neuroscience letters, 2017Co-Authors: Yu Wang, Gang Zhang, Rongrong Zhang, Xiangfeng Xing, Jia Guo, Fei Xie, Xinyue QinAbstract:Repulsive Guidance Molecule a (RGMa) has now emerged as a Molecule with pleiotropic roles, including repulsion, adhesion, migration and differentiation in the nervous system. In this study, adult male Sprague-Dawley (SD) rats received 90-min middle cerebral artery occlusion (MCAO) to observe RGMa/neogenin expression sites after ischemia/reperfusion injury and changes in angiogenesis after treatment with RNA interference using RGMa-specific recombinant adenovirus rAd5-shRNA-RGMa (rAd-shRGMa). To clarify how RGMa mediates angiogenesis, the RGMa function-blocking peptide six fibronectin type III (6FNIII) was also administered, and corresponding changes in vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang2), angiopoietin-1 (Ang1), and brain derived neurotrophic factor (BDNF) were determined by western blotting. Both RGMa and its receptor neogenin were expressed in neurons and vessel endothelial cells after ischemia/reperfusion injury, and angiogenesis, coupled with functional recovery, was enhanced after RNA interference against RGMa compared with the vehicle groups. VEGF, Ang2, Ang1 and BDNF expression levels were significantly increased after intervention with rAd-shRGMa or 6FNIII. Thus, RGMa might suppress angiogenesis via VEGF, Ang2, Ang1 and BDNF after cerebral ischemia/reperfusion injury, which has therapeutic potential by reducing these endogenous detrimental mechanisms.
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Repulsive Guidance Molecule a Inhibits Angiogenesis by Downregulating VEGF and Phosphorylated Focal Adhesion Kinase In Vitro.
Frontiers in neurology, 2017Co-Authors: Gang Zhang, Rong Wang, Ke Cheng, Yu Wang, Rongrong Zhang, Xinyue QinAbstract:Repulsive Guidance Molecule a (RGMa) is a major neuron Guidance factor in central nervous systems. We previously found that inhibition of RGMa could greatly enhance neural function rehabilitation in rats after MCAO/reperfusion. Neuron Guidance factors are often regulators of angiogenesis. However, the effect of RGMa on angiogenesis and its mechanisms remain to be determined. Here, we investigated the effect of RGMa on endothelial cell (EC) proliferation, migration, tube formation, and cytoskeleton reassembly. The addition of recombinant RGMa significantly decreased the proliferation, migration, and tube formation of ECs. It also decreased the level of phosphorylated focal adhesion kinase (p-FAK Tyr397). Furthermore, the F-actin of the cytoskeleton assembly was obviously suppressed, with decreased filopodia and lamellipodia after the addition of RGMa. Knockout of neogenin or Unc5b significantly diminished RGMa’s inhibition of EC migration, tube formation, and cytoskeleton reassembly. RGMa-induced p-FAK(Tyr397) decrease was also abolished by knockout of neogenin or Unc5b. These results indicate that RGMa may be a negative regulator of angiogenesis through down-regulating VEGF and p-FAK(Tyr397) via neogenin and Unc5b in vitro.
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RNA interference against Repulsive Guidance Molecule A improves axon sprout and neural function recovery of rats after MCAO/reperfusion.
Experimental neurology, 2012Co-Authors: Jinzhou Feng, Tianzhu Wang, Xinyue QinAbstract:Abstract Repulsive Guidance Molecule a (RGMa) is a neurite growth inhibitor that is of great interest in the study of CNS neuronal regeneration. We adopted RNA interference (RNAi) as a means of suppressing the expression of RGMa and observed the improvement in axonal regeneration and neurological function of rats after cerebral ischemic injury. Recombinant adenovirus rAd5-shRNA-RGMa was constructed and prepared for animal experimentation. RGMa and neurofilament protein 200 (NF200) in the ischemic cortex and ipsilateral hippocampus were detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The ischemic regions were examined by triphenyltetrazolium chloride (TTC) staining and the newborn neurite branches by Biotinylated Dextran Amine (BDA) neuronal tracing. Behavior tests were adopted to evaluate neurologic function recovery. Results showed RGMa was down-regulated and axonal growth was improved in the RNAi treated group (P
Herbert Y. Lin - One of the best experts on this subject based on the ideXlab platform.
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Repulsive Guidance Molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway.
Cellular signalling, 2016Co-Authors: Jiangfeng Liu, Yin Xia, Herbert Y. Lin, Weiling Wang, Ming Liu, Hong Zhou, Jianhua Ran, Baoxue YangAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive Guidance Molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD.
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Repulsive Guidance Molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). PLoS One 2012
2016Co-Authors: Chia Chi Sun, Herbert Y. Lin, Jodie L. BabittAbstract:Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily that exert their effects via type I and type II serine threonine kinase receptors and the SMAD intracellular signaling pathway to regulate diverse biologic processes. Recently, we discovered that the Repulsive Guidance Molecule (RGM) family, including RGMA, RGMB, and RGMC/hemojuvelin (HJV), function as co-receptors that enhance cellular responses to BMP ligands. Here, we use surface plasmon resonance to quantitate the binding kinetics of RGM proteins for BMP ligands. We show that among the RGMs, HJV exhibits the highest affinity for BMP6, BMP5, and BMP7 with KD 8.1, 17, and 20 nM respectively, versus 28, 33, and 166 nM for RGMB, and 55, 83, and 63 nM for RGMA. Conversely, RGMB exhibits preferential binding to BMP4 and BMP2 with KD 2.6 and 5.5 nM respectively, versus 4.5 and 9.4 nM for HJV, and 14 and 22 nM for RGMA, while RGMA exhibits the lowest binding affinity for most BMPs tested. Among the BMP ligands, RGMs exhibit the highest relative affinity for BMP4 and the lowest relative affinity for BMP7, while none of the RGMs bind to BMP9. Thus, RGMs exhibit preferential binding for distinct subsets of BMP ligands. The preferential binding of HJV for BMP6 is consistent with the functional role of HJV and BMP6 in regulating systemic iron homeostasis. Our data may help explain the mechanism by which BMPs exert cell-context specific effects via a limited number of type I and type II receptors
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Repulsive Guidance Molecule b (RGMb) Is Dispensable for Normal Gonadal Function in Mice
Biology of reproduction, 2016Co-Authors: Chenling Meng, Alan L Schneyer, Wenjing Liu, Huihui Huang, Yang Wang, Binbin Chen, Gordon J. Freeman, Herbert Y. Lin, Yin XiaAbstract:Bone morphogenetic protein (BMP) signaling plays an important role in spermatogenesis and follicle development. Our previous studies have shown that Repulsive Guidance Molecule b (RGMb, also known as Dragon) is a coreceptor that enhances BMP2 and BMP4 signaling in several cell types and that RGMb is expressed in spermatocytes and spermatids in the testis and in oocytes of the secondary follicles in the ovary. Here, we demonstrated that specific deletion of Rgmb in germ cells in the testis and ovary did not alter Smad1/5/8 phosphorylation, gonadal structures, and fertility. In addition, ovaries from postnatal global Rgmb knockout mice showed similar structures to the wild-type ovaries. Our results suggest that RGMb is not essential for normal gonadal function.
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Exhibit Differential Binding Kinetics for Bone
2016Co-Authors: Citable Link, Chia Chi Sun, Herbert Y. Lin, Jodie L. BabittAbstract:(Article begins on next page) The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Wu, Qifang, Chia Chi Sun, Herbert Y. Lin, and Jodie L. Babitt.2012. Repulsive Guidance Molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic protein
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dragon Repulsive Guidance Molecule rgmb inhibits e cadherin expression and induces apoptosis in renal tubular epithelial cells
Journal of Biological Chemistry, 2013Co-Authors: Wenjing Liu, Herbert Y. Lin, Baoxue Yang, Yueshui Zhao, Xiao-ming Meng, Chao Wan, Hui Y. Lan, Yin XiaAbstract:Dragon is one of the three members of the Repulsive Guidance Molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-β in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45–66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo. Background: Dragon is expressed in kidney tubular epithelial cells. Results: Dragon inhibits E-cadherin expression and induces apoptosis in IMCD3 cells, and Dragon+/− mice exhibit increased E-cadherin expression and decreased apoptosis in injured renal tubules. Conclusion: Dragon inhibits E-cadherin and induces apoptosis in renal tubular cells both in vitro and in vivo. Significance: Our results provide a novel mechanism underlying kidney injury.
Bernhard K. Mueller - One of the best experts on this subject based on the ideXlab platform.
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Levodopa increases oxidative stress and Repulsive Guidance Molecule A levels: a pilot study in patients with Parkinson’s disease
Journal of Neural Transmission, 2016Co-Authors: Thomas Müller, Isabel Trommer, Siegfried Muhlack, Bernhard K. MuellerAbstract:Exposure to free radicals influences synthesis, degradation and function of proteins, such as Repulsive Guidance Molecule A. Decay of this protein is essential for neuronal maintenance and recovery. Levodopa elevates oxidative stress. Therefore levodopa may impact Repulsive Guidance Molecule A metabolism. Objectives were to investigate plasma concentrations of Repulsive Guidance Molecule A, levodopa, cysteine and cysteinyl-glycine before and 1 h after levodopa application in patients with Parkinson’s disease. Cysteine and cysteinyl-glycine as biomarkers for oxidative stress exposure decreased, Repulsive Guidance Molecule A and levodopa rose. Repulsive Guidance Molecule A remained unchanged in levodopa naïve patients, but particularly went up in patients on a prior chronic levodopa regimen. Decay of cysteine specifically cysteinyl-glycine results from an elevated glutathione generation with rising cysteine consumption respectively from the alternative glutathione transformation to its oxidized form glutathione disulfide after free radical scavenging. Repulsive Guidance Molecule A rise may inhibit physiologic mechanisms for neuronal survival.
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Levodopa increases oxidative stress and Repulsive Guidance Molecule A levels: a pilot study in patients with Parkinson's disease.
Journal of neural transmission (Vienna Austria : 1996), 2016Co-Authors: Thomas Müller, Isabel Trommer, Siegfried Muhlack, Bernhard K. MuellerAbstract:Exposure to free radicals influences synthesis, degradation and function of proteins, such as Repulsive Guidance Molecule A. Decay of this protein is essential for neuronal maintenance and recovery. Levodopa elevates oxidative stress. Therefore levodopa may impact Repulsive Guidance Molecule A metabolism. Objectives were to investigate plasma concentrations of Repulsive Guidance Molecule A, levodopa, cysteine and cysteinyl-glycine before and 1 h after levodopa application in patients with Parkinson’s disease. Cysteine and cysteinyl-glycine as biomarkers for oxidative stress exposure decreased, Repulsive Guidance Molecule A and levodopa rose. Repulsive Guidance Molecule A remained unchanged in levodopa naive patients, but particularly went up in patients on a prior chronic levodopa regimen. Decay of cysteine specifically cysteinyl-glycine results from an elevated glutathione generation with rising cysteine consumption respectively from the alternative glutathione transformation to its oxidized form glutathione disulfide after free radical scavenging. Repulsive Guidance Molecule A rise may inhibit physiologic mechanisms for neuronal survival.
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Decreased levels of Repulsive Guidance Molecule A in association with beneficial effects of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients.
Journal of neural transmission (Vienna Austria : 1996), 2014Co-Authors: Thomas Müller, Stefan Barghorn, Isabel Trommer, Sven Lütge, Thomas Haas, Reinhold Mueller, Bjoern Gerlach, Gabi Öhm, Katrin Eilert, Bernhard K. MuellerAbstract:Repeated intrathecal application of the sustained release steroid triamcinolone acetonide is beneficial in progressive multiple sclerosis patients. Its putative regenerative effect may involve regulation of the Repulsive Guidance Molecule A synthesis. This protein inhibits axonal regeneration and functional recovery. Objectives were to demonstrate the efficacy of four triamcinolone applications every other day in association with Repulsive Guidance Molecule A levels in cerebrospinal fluid. Clinical evaluation was performed at baseline and on each day after a triamcinolone administration in 25 progressive multiple sclerosis patients. Repulsive Guidance Molecule A concentrations were determined before each triamcinolone application by western blot analysis with quantification. Clinical scores for multiple sclerosis improved, and the maximum walking distance and speed ameliorated in 17 patients. Repulsive Guidance Molecule A levels declined in these responders. The remaining patients showed no prompt clinical benefit and no decrease of Repulsive Guidance Molecule A concentrations. Decline of Repulsive Guidance Molecule A may reflect regeneration and functional recovery by triamcinolone in progressive multiple sclerosis patients.
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LIM-only protein 4 interacts directly with the Repulsive Guidance Molecule A receptor Neogenin.
Journal of Neurochemistry, 2008Co-Authors: Gregor Schaffar, Toshihide Yamashita, Axel Meyer, Martin Schmidt, Junko Taniguchi, Tanja Brodbeck, Bernhard K. MuellerAbstract:Repulsive Guidance Molecule A (RGM A) was recently described as a potent inhibitor of neuroregeneration in a rat spinal cord injury model. The receptor mediating RGM A's Repulsive activity was shown to be Neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of netrin receptors. Binding of RGM A to Neogenin induces activation of the small GTPase RhoA and of its effector Rho-kinase by an unknown mechanism. Here we show, that the cytoplasmic tail of Neogenin interacts directly with the transcriptional coactivator LIM domain only 4 (LMO4) in human SH-SY5Y cells, human Ntera neurons, and in embryonic rat cortical neurons. RGM A binding to Neogenin but not binding of Netrin-1, induces release of LMO4 from Neogenin. Down-regulation of LMO4 neutralizes the Repulsive activity of RGM A in neuronal cell lines and embryonic rat cortical neurons and prevents RhoA activation. These results show for the first time that an interaction of Neogenin with LMO4 is involved in the RGM A - Neogenin signal transduction pathway for RhoA activation.
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Myosin IIA is required for neurite outgrowth inhibition produced by Repulsive Guidance Molecule
Journal of neurochemistry, 2007Co-Authors: Takekazu Kubo, Katsuhiko Hata, Bernhard K. Mueller, Atsushi Yamaguchi, Mitsuharu Endo, Junko Taniguchi, Keiko Kitajo, Sayaka Tomura, Toshihide YamashitaAbstract:Although myelin-associated neurite outgrowth inhibitors express their effects through RhoA/Rho-kinase, the downstream targets of Rho-kinase remain unknown. We examined the involvement of myosin II, which is one of the downstream targets of Rho-kinase, by using blebbistatin - a specific myosin II inhibitor - and small interfering RNA targeting two myosin II isoforms, namely, MIIA and MIIB. We found that neurite outgrowth inhibition by Repulsive Guidance Molecule (RGMa) was mediated via myosin II, particularly MIIA, in cerebellar granule neurons. RGMa induced myosin light chain (MLC) phosphorylation by a Rho-kinase-dependent mechanism. After spinal cord injury in rats, phosphorylated MLC in axons around the lesion site was up-regulated, and this effect depends on Rho-kinase activity. Further, RGMa-induced F-actin reduction in growth cones and growth cone collapse were mediated by MIIA. We conclude that Rho-kinase-dependent activation of MIIA via MLC phosphorylation induces F-actin reduction and growth cone collapse and the subsequent neurite retraction/outgrowth inhibition triggered by RGMa.