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Lorena Caipo - One of the best experts on this subject based on the ideXlab platform.
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Slit neuronal secretion coordinates optic lobe morphogenesis in drosophila
Developmental Biology, 2020Co-Authors: Lorena Caipo, Constanza M Gonzalezramirez, Pablo Guzmanpalma, Esteban G Contreras, Tomas Palominos, Nicolas Fuenzalidauribe, Jorge M. Campusano, Bassem A Hassan, Jimena SierraltaAbstract:Abstract The complexity of the nervous system requires the coordination of multiple cellular processes during development. Among them, we find boundary formation, axon guidance, cell migration and cell segregation. Understanding how different cell populations such as glial cells, developing neurons and neural stem cells contribute to the formation of boundaries and morphogenesis in the nervous system is a critical question in neurobiology. Slit is an evolutionary conserved Protein essential for the development of the nervous system. For signaling, Slit has to bind to its cognate receptor Robo, a single-pass transmembrane Protein. Although the Slit/Robo signaling pathway is well known for its involvement in axon guidance, it has also been associated to boundary formation in the Drosophila visual system. In the optic lobe, Slit is expressed in glial cells, positioned at the boundaries between developing neuropils, and in neurons of the medulla ganglia. Although it has been assumed that glial cells provide Slit to the system, the contribution of the neuronal expression has not been tested. Here, we show that, contrary to what was previously thought, Slit Protein provided by medulla neurons is also required for boundary formation and morphogenesis of the optic lobe. Furthermore, tissue specific rescue using modified versions of Slit demonstrates that this Protein acts at long range and does not require processing by extracellular proteases. Our data shed new light on our understanding of the cellular mechanisms involved in Slit function in the fly visual system morphogenesis.
Jimena Sierralta - One of the best experts on this subject based on the ideXlab platform.
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Slit neuronal secretion coordinates optic lobe morphogenesis in drosophila
Developmental Biology, 2020Co-Authors: Lorena Caipo, Constanza M Gonzalezramirez, Pablo Guzmanpalma, Esteban G Contreras, Tomas Palominos, Nicolas Fuenzalidauribe, Jorge M. Campusano, Bassem A Hassan, Jimena SierraltaAbstract:Abstract The complexity of the nervous system requires the coordination of multiple cellular processes during development. Among them, we find boundary formation, axon guidance, cell migration and cell segregation. Understanding how different cell populations such as glial cells, developing neurons and neural stem cells contribute to the formation of boundaries and morphogenesis in the nervous system is a critical question in neurobiology. Slit is an evolutionary conserved Protein essential for the development of the nervous system. For signaling, Slit has to bind to its cognate receptor Robo, a single-pass transmembrane Protein. Although the Slit/Robo signaling pathway is well known for its involvement in axon guidance, it has also been associated to boundary formation in the Drosophila visual system. In the optic lobe, Slit is expressed in glial cells, positioned at the boundaries between developing neuropils, and in neurons of the medulla ganglia. Although it has been assumed that glial cells provide Slit to the system, the contribution of the neuronal expression has not been tested. Here, we show that, contrary to what was previously thought, Slit Protein provided by medulla neurons is also required for boundary formation and morphogenesis of the optic lobe. Furthermore, tissue specific rescue using modified versions of Slit demonstrates that this Protein acts at long range and does not require processing by extracellular proteases. Our data shed new light on our understanding of the cellular mechanisms involved in Slit function in the fly visual system morphogenesis.
Marc Tessierlavigne - One of the best experts on this subject based on the ideXlab platform.
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Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system
Neuron, 2002Co-Authors: Katja Brose, Corey S Goodman, Lynda Erskine, Andrew S Plump, Christelle Sabatier, Charles J Epstein, Carol A Mason, Marc TessierlavigneAbstract:Abstract During development, retinal ganglion cell (RGC) axons either cross or avoid the midline at the optic chiasm. In Drosophila , the Slit Protein regulates midline axon crossing through repulsion. To determine the role of Slit Proteins in RGC axon guidance, we disrupted Slit1 and Slit2 , two of three known mouse Slit genes. Mice defective in either gene alone exhibited few RGC axon guidance defects, but in double mutant mice a large additional chiasm developed anterior to the true chiasm, many retinal axons projected into the contralateral optic nerve, and some extended ectopically—dorsal and lateral to the chiasm. Our results indicate that Slit Proteins repel retinal axons in vivo and cooperate to establish a corridor through which the axons are channeled, thereby helping define the site in the ventral diencephalon where the optic chiasm forms.
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c elegans Slit acts in midline dorsal ventral and anterior posterior guidance via the sax 3 robo receptor
Neuron, 2001Co-Authors: Joe C Hao, Marc Tessierlavigne, Kazuko Fujisawa, Joseph G Culotti, Keiko Gengyoando, Shohei Mitani, Gary Moulder, Robert Barstead, Cornelia I BargmannAbstract:Robo receptors interact with ligands of the Slit family. The nematode C. elegans has one Robo receptor (SAX-3) and one Slit Protein (SLT-1), which direct ventral axon guidance and guidance at the midline. In larvae, slt-1 expression in dorsal muscles repels axons to promote ventral guidance. SLT-1 acts through the SAX-3 receptor, in parallel with the ventral attractant UNC-6 (Netrin). Removing both UNC-6 and SLT-1 eliminates all ventral guidance information for some axons, revealing an underlying longitudinal guidance pathway. In the embryo, slt-1 is expressed at high levels in anterior epidermis. Embryonic expression of SLT-1 provides anterior-posterior guidance information to migrating CAN neurons. Surprisingly, slt-1 mutants do not exhibit the nerve ring and epithelial defects of sax-3 mutants, suggesting that SAX-3 has both Slit-dependent and Slit-independent functions in development.
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biochemical purification of a mammalian Slit Protein as a positive regulator of sensory axon elongation and branching
Cell, 1999Co-Authors: Kuan Hong Wang, Katja Brose, Thomas Kidd, Corey S Goodman, David Arnott, William J Henzel, Marc TessierlavigneAbstract:Many neurons in both vertebrates and invertebrates innervate multiple targets by sprouting secondary axon collaterals (or branches) from a primary axon shaft. To begin to identify molecular regulators of axon branch initiation or extension, we studied the growth of single sensory axons in an in vitro collagen assay system and identified an activity in extracts of embryonic spinal cord and of postnatal and adult brain that promotes the elongation and formation of extensive branches by these axons. Biochemical purification of the activity from calf brain extracts led to the identification of an amino-terminal fragment of Slit2 as the main active component and to the discovery of a distinct activity that potentiates its effects. These results indicate that Slit Proteins may function as positive regulators of axon collateral formation during the establishment or remodeling of neural circuits.
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Slit Proteins bind robo receptors and have an evolutionarily conserved role in repulsive axon guidance
Cell, 1999Co-Authors: Katja Brose, Corey S Goodman, Marc Tessierlavigne, Kuan Hong Wang, David Arnott, William J Henzel, Kimberly S Bland, Thomas KiddAbstract:Extending axons in the developing nervous system are guided in part by repulsive cues. Genetic analysis in Drosophila, reported in a companion to this paper, identifies the Slit Protein as a candidate ligand for the repulsive guidance receptor Roundabout (Robo). Here we describe the characterization of three mammalian Slit homologs and show that the Drosophila Slit Protein and at least one of the mammalian Slit Proteins, Slit2, are proteolytically processed and show specific, high-affinity binding to Robo Proteins. Furthermore, recombinant Slit2 can repel embryonic spinal motor axons in cell culture. These results support the hypothesis that Slit Proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors.
Yi Rao - One of the best experts on this subject based on the ideXlab platform.
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modulation of inflammation by Slit Protein in vivo in experimental crescentic glomerulonephritis
American Journal of Pathology, 2004Co-Authors: Yi Rao, John Kanellis, Gabriela E Garcia, Gustavo Parra, Curtis B Wilson, Suhua Han, Wayne C Smith, Richard J Johnson, Lili FengAbstract:A basic conservation of cell migration guidance mechanisms in the nervous and immune systems was proposed when Slit, known for its role in axon guidance, was found to inhibit chemokine-induced leukocyte chemotaxis in vitro. These studies examined the role of Slit2 in modulating inflammation in vivo. In a rat model of glomerulonephritis, endogenous glomerular Slit2 expression fell after disease induction, and its inhibition during the early disease period accelerated inflammation. Ex vivo glomerular leukocytes showed decreased chemokine and chemoattractant-induced chemotaxis in response to Slit2, suggesting an anti-inflammatory role for glomerular Slit2. In contrast to the effect of inhibition, glomerulonephritis was ameliorated by systemic Slit2 administration. Slit2 treatment improved disease histologically and also improved renal function when given early in the disease course. Leukocytes harvested from rats receiving Slit2 showed decreased monocyte chemoattractant Protein-1 (MCP)-1-mediated migration, consistent with a peripheral Slit2 effect. In keeping with this functional alteration, Slit2-mediated inhibition of RAW264.7 cell chemotaxis was associated with decreased levels of active cdc42 and Rac1, implicating GTPases in leukocyte Slit2 signaling. These findings suggest a role for endogenous Slit2 in the inhibition of chemoattractant-mediated signals, demonstrate a potentially important anti-inflammatory effect for Slit2 in vivo, and provide further evidence for conserved mechanisms guiding the process of migration in distinct cell types.
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the n terminal leucine rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neurons
The Journal of Neuroscience, 2001Co-Authors: Jin Hui Chen, Sophie Dupuis, Leng Wen, Yi RaoAbstract:The Slit Proteins are a new family of secreted guidance cues involved in axon guidance and neuronal migration. Each mammalian Slit Protein contains >1400 amino acid residues, with four leucine-rich regions (LRRs), nine epidermal growth factor repeats, a laminin G domain, and a C-terminal cysteine-rich domain. A receptor for Slit is the transmembrane Protein Roundabout (Robo), whose extracellular part contains five Ig domains and three fibronectin type III repeats. We report here that the LRRs in Slit are sufficient for binding to the Ig domains of Robo. Mutant forms of Slit containing only the LRRs function as chemorepellents for axons projecting from the olfactory bulb both in vitro and in the telencephalon. The LRRs can repel neurons migrating from the anterior subventricular zone (SVZa) to the olfactory bulb in brain slices isolated from neonatal rodents. However, the LRRs do not show repulsive effects on the SVZa neurons migrating in collagen gels. Our results indicate that the same LRRs are sufficient for guiding both axon projection and neuronal migration and suggest that the other regions in the Slit Proteins may be involved in regulating the diffusion and distribution of the Slit Proteins. The fact that the same domains are involved in guiding axon projection and neuronal migration further strengthens the idea of a conserved guidance mechanism for these important processes.
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vertebrate Slit a secreted ligand for the transmembrane Protein roundabout is a repellent for olfactory bulb axons
Cell, 1999Co-Authors: Jin Hui Chen, Tanya Fagaly, Lijuan Zhou, Wenlin Yuan, Sophie Dupuis, Zhihong Jiang, William E Nash, Carrie Gick, David M Ornitz, Yi RaoAbstract:The olfactory bulb plays a central role in olfactory information processing through its connections with both peripheral and cortical structures. Axons projecting from the olfactory bulb to the telencephalon are guided by a repulsive activity in the septum. The molecular nature of the repellent is not known. We report here the isolation of vertebrate homologs of the Drosophila Slit gene and show that Slit Protein binds to the transmembrane Protein Roundabout (Robo). Slit is expressed in the septum whereas Robe is expressed in the olfactory bulb. Functionally, Slit acts as a chemorepellent for olfactory bulb axons. These results establish a ligand-receptor relationship between two molecules important for neural development, suggest a role for Slit in olfactory bulb axon guidance, and reveal the existence of a new family of axon guidance molecules.
Krishna Moorthi Bhat - One of the best experts on this subject based on the ideXlab platform.
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post guidance signaling by extracellular matrix associated Slit Slit n maintains fasciculation and position of axon tracts in the nerve cord
PLOS Genetics, 2017Co-Authors: Krishna Moorthi BhatAbstract:Axon-guidance by Slit-Roundabout (Robo) signaling at the midline initially guides growth cones to synaptic targets and positions longitudinal axon tracts in discrete bundles on either side of the midline. Following the formation of commissural tracts, Slit is found also in tracts of the commissures and longitudinal connectives, the purpose of which is not clear. The Slit Protein is processed into a larger N-terminal peptide and a smaller C-terminal peptide. Here, I show that Slit and Slit-N in tracts interact with Robo to maintain the fasciculation, the inter-tract spacing between tracts and their position relative to the midline. Thus, in the absence of Slit in post-guidance tracts, tracts de-fasciculate, merge with one another and shift their position towards the midline. The Slit Protein is proposed to function as a gradient. However, I show that Slit and Slit-N are not freely present in the extracellular milieu but associated with the extracellular matrix (ECM) and both interact with Robo1. Slit-C is tightly associated with the ECM requiring collagenase treatment to release it, and it does not interact with Robo1. These results define a role for Slit and Slit-N in tracts for the maintenance and fasciculation of tracts, thus the maintenance of the hardwiring of the CNS.
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The expression of Slit is progressively lost from the midline and tracts in an anterior-posterior direction in ptc mutant embryos.
2017Co-Authors: Krishna Moorthi BhatAbstract:(A, B):Wild-type embryos were examined for Slit transcription by RNA whole mount in situ (alkaline phosphatase, AP) and Slit Protein (anti-Slit-C) by DAB-histochemistry. The image analysis was done using the ImageJ software and shown as expression profile plot. The yellow-rectangle in the inset photomicrograph marks the area of ImageJ analysis. The Slit transcription is restricted to the midline glia, and the Slit Protein is present in midline glia as well as in axon tracts of commissures and longitudinal connectives. Scale bar: Panel A, 10 μm; panel B, 8 μm. (C, D): Wild-type embryos were stained with anti-Slit-C and the signals were detected using a fluorescently labeled secondary antibody and confocal microscopy (C, single section-plane), or stained with anti-Slit-N and detected with DAB-histochemistry (D). Note the presence of Slit in commissures and connectives. AC, anterior commissure; PC, posterior commissure; LC, longitudinal connectives. Scale bar: 8 μm. (E): The expression of Slit RNA in 10 hpf wild-type and ptc mutant embryos. No loss of Slit expression is detected at this age. Scale bar: 8 μm. (F): The expression of Slit mRNA and Protein in 14 hpf wild-type and 14.5 hpf old ptc mutant embryos. The expression (both the mRNA and the Protein) is progressively lost from the midline as well as from the tracts in an anterior-posterior direction (compare panel F to panel B). Scale bar: 8 μm. (G): In a minority of ptc embryos, loss of Slit expression was less organized, although the posterior region was more affected. In such embryos as well, the narrowing of tracts phenotype correlated with the loss of abundance of Slit in tracts. Scale bar: 8 μm.
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Post-guidance signaling by extracellular matrix-associated Slit/Slit-N maintains fasciculation and position of axon tracts in the nerve cord
2017Co-Authors: Krishna Moorthi BhatAbstract:Axon-guidance by Slit-Roundabout (Robo) signaling at the midline initially guides growth cones to synaptic targets and positions longitudinal axon tracts in discrete bundles on either side of the midline. Following the formation of commissural tracts, Slit is found also in tracts of the commissures and longitudinal connectives, the purpose of which is not clear. The Slit Protein is processed into a larger N-terminal peptide and a smaller C-terminal peptide. Here, I show that Slit and Slit-N in tracts interact with Robo to maintain the fasciculation, the inter-tract spacing between tracts and their position relative to the midline. Thus, in the absence of Slit in post-guidance tracts, tracts de-fasciculate, merge with one another and shift their position towards the midline. The Slit Protein is proposed to function as a gradient. However, I show that Slit and Slit-N are not freely present in the extracellular milieu but associated with the extracellular matrix (ECM) and both interact with Robo1. Slit-C is tightly associated with the ECM requiring collagenase treatment to release it, and it does not interact with Robo1. These results define a role for Slit and Slit-N in tracts for the maintenance and fasciculation of tracts, thus the maintenance of the hardwiring of the CNS.