共查询到20条相似文献,搜索用时 0 毫秒
1.
Rajagopalan S Deitinghoff L Davis D Conrad S Skutella T Chedotal A Mueller BK Strittmatter SM 《Nature cell biology》2004,6(8):756-762
Repulsive guidance molecule (RGM) is a recently identified protein implicated in both axonal guidance and neural tube closure. The avoidance of chick RGM in the posterior optic tectum by growing temporal, but not nasal, retinal ganglion cell axons is thought to contribute to visual map formation. In contrast to ephrins, semaphorins, netrins and slits, no receptor mechanism for RGM action has been defined. Here, an expression cloning strategy identified neogenin as a binding site for RGM, with a sub-nanomolar affinity. Consistent with selective axonal responsiveness to RGM, neogenin is expressed in a gradient across the chick retina. Neogenin is known to be one of several netrin-binding proteins but only neogenin interacts with RGM. The avoidance of RGM by temporal retinal axons is blocked by the anti-neogenin antibody and the soluble neogenin ectodomain. Dorsal root ganglion axons are unresponsive to RGM but are converted to a responsive state by neogenin expression. Thus, neogenin functions as an RGM receptor. 相似文献
2.
Suda M Hata K Sawada A Nakamura Y Kubo T Yamaguchi A Yamashita T 《Biochemical and biophysical research communications》2008,371(3):501-504
Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system [T. Yamashita, B.K. Mueller, K. Hata, Neogenin and RGM signaling in the central nervous system, Curr. Opin. Neurobiol. 17 (2007) 29-34]. Functional studies in Xenopus and chick embryos have revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos have demonstrated its function in regulating the cephalic neural tube closure. Importantly, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we identified two RGMa-derived peptides that functioned as antagonists against RGMa. The peptides studied in vitro dose-dependently suppressed the neurite growth inhibition and growth cone collapse induced by RGMa. Thus, these peptides are promising reagents to treat injuries of the central nervous system. 相似文献
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The repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system. Functional studies have revealed that it has roles in axon guidance and laminar patterning in Xenopus and chick embryos, and in controlling cephalic neural tube closure in mouse embryos. The recent identification of neogenin as a receptor for RGM has provided evidence of the diverse functions of this ligand-receptor pair. Re-expression of RGM is observed after injury in the adult human and rat central nervous systems. Inhibition of RGM enhances growth of injured axons and promotes functional recovery after spinal cord injury in rats. Thus, re-expression of embryonic repulsive cues in adult tissues contributes to failure of axon regeneration in the central nervous system. 相似文献
5.
Katsuhiko Hata Kozo Kaibuchi Shinobu Inagaki Toshihide Yamashita 《The Journal of cell biology》2009,184(5):737-750
Neuronal axons are guided by attractive and repulsive cues in their local environment. Because the repulsive guidance molecule A (RGMa) was originally identified as an axon repellent in the visual system, diverse functions in the developing and adult central nervous system have been ascribed to it. RGMa binding to its receptor neogenin induces RhoA activation, leading to inhibitory/repulsive behavior and collapse of the neuronal growth cone. However, the precise mechanisms that regulate RhoA activation are poorly understood. In this study, we show that Unc5B, a member of the netrin receptor family, interacts with neogenin as a coreceptor for RGMa. Moreover, leukemia-associated guanine nucleotide exchange factor (LARG) associates with Unc5B to transduce the RhoA signal. Focal adhesion kinase (FAK) is involved in RGMa-induced tyrosine phosphorylation of LARG as well as RhoA activation. These findings uncover the molecular basis for diverse functions mediated by RGMa. 相似文献
6.
Xia Y Cortez-Retamozo V Niederkofler V Salie R Chen S Samad TA Hong CC Arber S Vyas JM Weissleder R Pittet MJ Lin HY 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(3):1369-1376
Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-γ and TNF-α. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN-γ, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-γ and suggesting them as possible therapeutic tools against IA. 相似文献
7.
Myosin IIA is required for neurite outgrowth inhibition produced by repulsive guidance molecule 总被引:1,自引:0,他引:1
Kubo T Endo M Hata K Taniguchi J Kitajo K Tomura S Yamaguchi A Mueller BK Yamashita T 《Journal of neurochemistry》2008,105(1):113-126
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. 相似文献
8.
Yoshida J Kubo T Yamashita T 《Biochemical and biophysical research communications》2008,372(4):725-729
Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system. Functional studies in Xenopus and chick embryos revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos demonstrated its function in regulating cephalic neural tube closure. Moreover, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we demonstrate in vitro that RGMa, an RGM homolog, inhibits neurite growth and cortical neuron branching on mouse embryonic day 16. Further, exposure of cultured neurons to RGMa significantly reduced the number of colocalized immunoreactive clusters of synapsin 1 and PSD-95 in the spines. This RGMa-mediated inhibition of the assembly of presynaptic and postsynaptic components suggests a role of RGMa in inhibiting mature synapse formation. Thus, RGMa may negatively regulate neuronal network formation in cortical neurons. 相似文献
9.
Iftekhar Bin Naser Yuhong Su Shahidul M. Islam Yohei Shinmyo Sanbing Zhang Giasuddin Ahmed Sandy Chen 《Developmental biology》2009,332(2):351-359
The mesencephalic V neurons and tectobulbar axons in chick embryo project over long distances that appear during the early development of the chick optic tectum. The mesencephalic V neuron and tectobulbar axonal growth begin at Hamburger and Hamilton stage 14 and stage 18, respectively. Both fibers proceed downward from the dorsal to the ventral side of the lateral wall of the optic tectum and then turn caudally and join the medial longitudinal fasciculus. Their axons appear in the most superficial layer of the tectum at early stages and do not cross the dorsal midline of the tectum. Here, we report the role of draxin, a recently identified axon guidance protein, in the formation of the ventrally directed tectum axonal tracts in chicken embryo. draxin is expressed in a high dorsal to low ventral gradient in chick optic tectum. In vitro experiments show that draxin repels neurite outgrowth from dorsal tectum explants. In vivo overexpression resulted in inhibition or misrouting of axon growth in the tectum. Therefore, draxin may be an important member of the collection of repulsive guidance molecules that regulate the formation of the ventrally directed tectum axon tracts. 相似文献
10.
Kolodkin AL 《Trends in cell biology》1996,6(1):15-22
During development, neuronal growth cones encounter a variety of guidance cues while mediating axon path finding, target recognition and synapse formation. It is clear that repulsive guidance mechanisms play an essential role in these processes. The semaphorin gene family, which is conserved from invertebrates to mammals, includes members that mediate repulsive guidance. Molecular and cellular analysis of this gene family is providing insight into how inhibitory cues function during neurodevelopment. 相似文献
11.
Repulsive guidance molecule (RGM) a is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein that has been
implicated in chemorepulsive axon guidance. Although RGMa binds the transmembrane receptor Neogenin, the developmental events
controlled by the RGMa-Neogenin interactions in vivo remain largely unknown. We have cloned full-length RGMa from Xenopus borealis for the first time and identified two homologous genes referred to as RGMa1 and RGMa2. Here we show RGMa1 overexpression
at 2-cell-stage resulted in cell death, which lead to an early embryonic lethal phenotype of the embryos. Time-lapse photomicroscopy
revealed that embryos began to show initial morphological defects from ∼5 h post-fertilization (hpf) which was then followed
by extensive blastomere cell death at ∼11 hpf. This phenotype was rescued by simultaneous knock down of RGMa using translation
blocking anti-sense morpholinos. Knock down of the RGMa1 receptor Neogenin in RGMa1 overexpressing embryos was also able to
rescue the phenotype. Together these results indicated that RGMa1 was signalling through Neogenin to induce cell death in
the early embryo. While previous studies have suggested that Neogenin is a dependence receptor that induces cell death in
the absence of RGM, we have instead shown that Neogenin-RGM interactions induce cell death in the early embryo. The roles
of RGMa1 and Neogenin appear to be context specific so that their co-ordinated and regulated expressions are essential for
normal development of the vertebrate embryo. 相似文献
12.
《Cell Adhesion & Migration》2013,7(2):85-90
RGMa (repulsive guidance molecule a) was the first identified molecule that possessed the necessary functional activity to repulse and steer growth cones to their target in the brain. By binding to its neogenin receptor, RGMa caused the collapse of growth cones and encouraged axons to grow along specific trajectories in vitro. Although originally characterized in 1990, RGMa was not conclusively shown to mediate axon guidance in vivo for another 12 years. Loss-of-function analysis in mice revealed that RGMa may play a more important role in neural tube morphogenesis. RGMa has now emerged as a molecule with pleiotropic roles involving cell adhesion, cell migration, cell polarity and cell differentiation which together strongly influence early morphogenetic events as well as immune responses. RGMa can be regarded as a molecule for all seasons. 相似文献
13.
RGMa (repulsive guidance molecule a) was the first identified molecule that possessed the necessary functional activity to repulse and steer growth cones to their target in the brain. By binding to its neogenin receptor, RGMa caused the collapse of growth cones and encouraged axons to grow along specific trajectories in vitro. Although originally characterized in 1990, RGMa was not conclusively shown to mediate axon guidance in vivo for another 12 years. Loss-of-function analysis in mice revealed that RGMa may play a more important role in neural tube morphogenesis. RGMa has now emerged as a molecule with pleiotropic roles involving cell adhesion, cell migration, cell polarity and cell differentiation which together strongly influence early morphogenetic events as well as immune responses. RGMa can be regarded as a molecule for all seasons. 相似文献
14.
Using the hydrophobic fluorescent dye 8-anilino-1-naphthalenesulfonic acid (8-ANS), a hydrophobic site on the surface of the protein globule of angiotensin-converting enzyme (ACE) from bovine lung was found. The dissociation constant of the ACE–8-ANS complex was estimated as 1.5 ± 0.2 M. This hydrophobic site is far from the ACE catalytic sites because the binding of the hydrophobic dye does not influence ACE activity. Shielding of the ACE hydrophobic site due to the complex formation with 8-ANS or Triton X-100 resulted in pronounced stabilization of the enzyme against the action of water radiolysis products during -irradiation of dilute solutions of ACE. 相似文献
15.
We have characterized for the first time the mouse expression patterns of the three known members of the novel RGM gene family ('Repulsive Axonal Guidance molecules' A, B and C) by in situ hybridization. Both RGM A and B are mostly expressed in central nervous system, while RGM C is exclusively expressed in all striated muscle and in the myocardium. RGM A and B appear at every level of the developing neural axis, where they colocalize to a large extent in the mantle layer, although only RGM A appears in the neuroepithelium, and only RGM B in the peripheral nervous system. During development, both RGM A and B appear also in lung and in limb cartilage, while RGM B has additional expression domains in pancreas. 相似文献
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M Yoshida G Fuse T Matsui S Ouchi 《Biochemical and biophysical research communications》1992,188(2):794-798
It has been believed that Dictyostelium discoideum cell membranes contain no sialic acid. In this study, however, we found that contact site A, the cell adhesion molecule of D. discoideum, is a major glycoprotein containing sialic acids. This suggests that sialic acid in non-reducing terminal plays an important role in the cell adhesion in which contact site A is involved. 相似文献
18.
Mueller BK Yamashita T Schaffar G Mueller R 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2006,361(1473):1513-1529
During the development of the nervous system, outgrowing axons often have to travel long distances to reach their target neurons. In this process, outgrowing neurites tipped with motile growth cones rely on guidance cues present in their local environment. These cues are detected by specific receptors expressed on growth cones and neurites and influence the trajectory of the growing fibres. Neurite growth, guidance, target innervation and synapse formation and maturation are the processes that occur predominantly but not exclusively during embryonic or early post-natal development in vertebrates. As a result, a functional neural network is established, which is usually remarkably stable. However, the stability of the neural network in higher vertebrates comes at an expensive price, i.e. the loss of any significant ability to regenerate injured or damaged neuronal connections in their central nervous system (CNS). Most importantly, neurite growth inhibitors prevent any regenerative growth of injured nerve fibres. Some of these inhibitors are associated with CNS myelin, others are found at the lesion site and in the scar tissue. Traumatic injuries in brain and spinal cord of mammals induce upregulation of embryonic inhibitory or repulsive guidance cues and their receptors on the neurites. An example for embryonic repulsive directional cues re-expressed at lesion sites in both the rat and human CNS is provided with repulsive guidance molecules, a new family of directional guidance cues. 相似文献
19.
L Serrano A Valencia R Caballero J Avila 《The Journal of biological chemistry》1986,261(15):7076-7081
Tubulin is a calcium-binding protein. Two different modes of interaction of calcium with tubulin have been described: a high affinity interaction to one or two binding sites and lower affinity interactions to several other binding sites. In the present study, we have used limited proteolysis of tubulin with trypsin, chymotrypsin, and subtilisin to localize the high affinity calcium-binding sites. Our results indicate that two sites are located in the carboxyl-terminal region of both tubulin subunits, and that tubulin deprived of its carboxyl-terminal region is able to polymerize in the presence of 0.5 mM calcium. 相似文献
20.
The calcium-dependent cell-adhesion molecule uvomorulin is a member of the cadherin gene family. Recent studies on the homophilic binding of molecules from neighbouring cells have shown that the amino-terminal part of these proteins plays an important role in the adhesive mechanism. We show here that the epitope for monoclonal antibody DECMA-1, capable of blocking uvomorulin function, is located close to the membrane proximal part of the extracellular domain. To test the effect of structural changes in this membrane proximal region on the adhesive function of uvomorulin, we have studied the cluster of cysteine residues located in the vicinity of the DECMA-1 epitope. Treatment of cells with the reducing agent dithiothreitol (DTT) cleaved the di-sulphide bonds in uvomorulin and affected the adhesive properties of cells. Close cell-cell contacts accompanied by cell flattening and changes in cell shape were blocked by DTT; however, cell aggregation was not inhibited. Consistent with this, uvomorulin became more susceptible in its membrane proximal part to trypsin digestion after treatment with DTT, indicating that conformational changes in this region of the molecule affect the adhesive function. These results suggest that the membrane proximal region of uvomorulin is involved in the adhesive mechanism. 相似文献