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Sarah Guthrie - One of the best experts on this subject based on the ideXlab platform.
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patterning and Axon guidance of cranial Motor neurons
Nature Reviews Neuroscience, 2007Co-Authors: Sarah GuthrieAbstract:The cranial Motor nerves control muscles involved in eye, head and neck movements, feeding, speech and facial expression. The generic and specific properties of cranial Motor neurons depend on a matrix of rostrocaudal and dorsoventral patterning information. Repertoires of transcription factors, including Hox genes, confer generic and specific properties on Motor neurons, and endow subpopulations at various axial levels with the ability to navigate to their targets. Cranial Motor Axon projections are guided by diffusible cues and aided by guideposts, such as nerve exit points, glial cells and muscle primordia. The recent identification of genes that are mutated in human cranial dysinnervation disorders is now shedding light on the functional consequences of perturbations of cranial Motor neuron development.
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Ephrin-As play a rhombomere-specific role in trigeminal Motor Axon projections in the chick embryo
Developmental biology, 2005Co-Authors: Fabrice Prin, Uma Thaker, Uwe Drescher, Sarah GuthrieAbstract:In this study, we investigate the possible role of ephrin–Eph signaling in trigeminal Motor Axon projections. We find that EphA receptors are expressed at higher levels by rhombomere 2 (r2) trigeminal Motor neurons than by r3 trigeminal Motor neurons in the chick embryo. Mapping of rhombomere-specific Axon projections shows that r2 and r3 trigeminal Motor neurons project to different muscle targets, including the mandibular adductor and the intermandibularis muscles respectively. Ephrin-A5 is expressed in these muscles, especially in some regions of the intermandibularis muscle, and can cause growth cone collapse of both r2 and r3 Motor Axons in vitro. We demonstrate that in vivo overexpression of ephrin-A5 in the intermandibularis muscle, or overexpression of dominant-negative EphA receptors in trigeminal Motor neurons leads to a reduction in branching of r3-derived Motor Axons specifically. Overexpression of full-length EphA receptors impairs the formation of r3 projections to the intermandibularis muscle. These findings indicate that ephrins and their Eph receptors play a role in trigeminal Motor Axon topographic mapping and in rhombomere 3-derived projections in particular.
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Rhombomere origin plays a role in the specificity of cranial Motor Axon projections in the chick.
The European journal of neuroscience, 1999Co-Authors: Joanne Warrilow, Sarah GuthrieAbstract:Guidance of cranial Motor Axons to their targets conforms to a segmental plan in the chick embryo. Trigeminal Motor neurons lie within rhombomeres 2 and 3 and project via an exit point in rhombomere 2 to innervate the first branchial arch. Facial Motor neurons lie within rhombomeres 4 and 5 and grow out via an exit point in rhombomere 4 to innervate the second branchial arch. We have investigated the axial level-specific matching of Motor neurons and branchial arches using donor to host transplantation in avian embryos. Previous work has shown that rostrocaudal reversal of a single hindbrain segment (rhombomere 3) leads to misprojection of a contingent of trigeminal Axons via the facial nerve exit point. Using the same experimental manipulation in chick embryos and quail–chick chimaeras, we have analysed the pathways of these aberrant projections. We have found that in the majority of embryos analysed from stage 19 to 31, trigeminal Axons from the transplanted rhombomere projected towards second branchial arch muscles, in addition to their normal first arch muscle targets. However, from stage 32 to 36, aberrant projections to second arch-derived muscles were detected only in a small minority of embryos. These experiments show that trigeminal Motor neurons show a lack of specificity in their early projection into the periphery but that inappropriate projections may be later eliminated. This suggests that segmental mechanisms intrinsic to the hindbrain specify Motor neurons with respect to their eventual innervation pattern.
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Motor Axon subpopulations respond differentially to the chemorepellents netrin 1 and semaphorin d
Neuron, 1997Co-Authors: Alfredo Varelaechavarria, Anna Tucker, Andreas W Puschel, Sarah GuthrieAbstract:During development, growing Motor Axons are excluded from the ventral midline of the neural tube by diffusible chemorepellents emanating from this region. Molecular candidates for this chemorepellent activity include semaphorin D and netrin-1; the latter is known to repel trochlear Motor Axons. Qualitatively or quantitatively different responses to these molecules might underlie the initial deflection from the midline and subsequent segregation of Motor Axon trajectories. To test this idea, we have cocultured cell aggregates secreting netrin-1 or semaphorin D at a distance from tissue explants containing different Motor neuron subpopulations, in collagen gels. Cranial Motor Axons that project dorsally in vivo such as those of the trigeminal, facial, and glossopharyngeal nuclei were repelled by both netrin-1 and semaphorin D. By contrast, ventrally projecting spinal Motor Axons and abducens Axons were not affected by netrin-1. Spinal and abducens Motor neurons also responded to semaphorin D. The ventrally projecting Axons of oculoMotor neurons were not repelled by netrin-1 or semaphorin D. Differential responsiveness to netrin-1 and semaphorin D could thus contribute to the generation of dorsal and ventral Motor Axon pathways during development.
Alex L Kolodkin - One of the best experts on this subject based on the ideXlab platform.
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distinct roles for secreted semaphorin signaling in spinal Motor Axon guidance
Neuron, 2005Co-Authors: Andrea B Huber, Artur Kania, Tracy S Tran, Natalia V De Marco Garcia, Ivo Lieberam, Dontais Johnson, Thomas M Jessell, David D Ginty, Alex L KolodkinAbstract:Neuropilins, secreted semaphorin coreceptors, are expressed in discrete populations of spinal Motor neurons, suggesting they provide critical guidance information for the establishment of functional Motor circuitry. We show here that Motor Axon growth and guidance are impaired in the absence of Sema3A-Npn-1 signaling. Motor Axons enter the limb precociously, showing that Sema3A controls the timing of Motor Axon in-growth to the limb. Lateral Motor column (LMC) Motor Axons within spinal nerves are defasciculated as they grow toward the limb and converge in the plexus region. Medial and lateral LMC Motor Axons show dorso-ventral guidance defects in the forelimb. In contrast, Sema3F-Npn-2 signaling guides the Axons of a medial subset of LMC neurons to the ventral limb, but plays no major role in regulating their fasciculation. Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of Motor Axon growth and guidance during the formation of spinal Motor connections.
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semaphorin 1a acts in concert with the cell adhesion molecules fasciclin ii and connectin to regulate Axon fasciculation in drosophila
Genetics, 2000Co-Authors: Alex S Huang, Alex L KolodkinAbstract:Semaphorins comprise a large family of phylogenetically conserved secreted and transmembrane glycoproteins, many of which have been implicated in repulsive Axon guidance events. The transmembrane semaphorin Sema-1a in Drosophila is expressed on Motor Axons and is required for the generation of neuromuscular connectivity. Sema-1a can function as an Axonal repellent and mediates Motor Axon defasciculation. Here, by manipulating the levels of Sema-1a and the cell adhesion molecules fasciclin II (Fas II) and connectin (Conn) on Motor Axons, we provide further evidence that Sema-1a mediates Axonal defasciculation events by acting as an Axonally localized repellent and that correct Motor Axon guidance results from a balance between attractive and repulsive guidance cues expressed on Motor neurons.
Coralie Fassier - One of the best experts on this subject based on the ideXlab platform.
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BMP- and neuropilin 1-mediated Motor Axon navigation relies on spastin alternative translation
Development (Cambridge England), 2018Co-Authors: Nicolas Jardin, Rachel Allison, Evan Reid, Corinne Houart, Jamilé Hazan, François Giudicelli, Daniel Ten Martín, Anaïs Vitrac, Stéphanie De Gois, Coralie FassierAbstract:Functional analyses of genes responsible for neurodegenerative disorders have unveiled crucial links between neurodegenerative processes and key developmental signalling pathways. Mutations in SPG4-encoding spastin cause hereditary spastic paraplegia (HSP). Spastin is involved in diverse cellular processes that couple microtubule severing to membrane remodelling. Two main spastin isoforms are synthesised from alternative translational start sites (M1 and M87). However, their specific roles in neuronal development and homeostasis remain largely unknown. To selectively unravel their neuronal function, we blocked spastin synthesis from each initiation codon during zebrafish development and performed rescue analyses. The knockdown of each isoform led to different Motor neuron and locomotion defects, which were not rescued by the selective expression of the other isoform. Notably, both morphant neuronal phenotypes were observed in a CRISPR/Cas9 spastin mutant. We next showed that M1 spastin, together with HSP proteins atlastin 1 and NIPA1, drives Motor Axon targeting by repressing BMP signalling, whereas M87 spastin acts downstream of neuropilin 1 to control Motor neuron migration. Our data therefore suggest that defective BMP and neuropilin 1 signalling may contribute to the Motor phenotype in a vertebrate model of spastin depletion.
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Zebrafish atlastin controls motility and spinal Motor Axon architecture via inhibition of the BMP pathway
Nature Neuroscience, 2010Co-Authors: Coralie Fassier, James A. Hutt, Steffen Scholpp, Andrew Lumsden, Bruno Giros, Fatiha Nothias, Sylvie Schneider-maunoury, Corinne Houart, Jamilé HazanAbstract:To better understand hereditary spastic paraplegia (HSP), we characterized the function of atlastin, a protein that is frequently involved in juvenile forms of HSP, by analyzing loss- and gain-of-function phenotypes in the developing zebrafish. We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal Motor Axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway. Overexpression analyses confirmed that atlastin inhibits BMP signaling. In primary cultures of zebrafish spinal neurons, Atlastin partially colocalized with type I BMP receptors in late endosomes distributed along neurites, which suggests that atlastin may regulate BMP receptor trafficking. Finally, genetic or pharmacological inhibition of BMP signaling was sufficient to rescue the loss of mobility and spinal Motor Axon defects of atl1 morphants, emphasizing the importance of fine-tuning the balance of BMP signaling for vertebrate Motor Axon architecture and stability.
Kai Zinn - One of the best experts on this subject based on the ideXlab platform.
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a gain of function screen for genes controlling Motor Axon guidance and synaptogenesis in drosophila
Current Biology, 2001Co-Authors: Rachel Kraut, Kaushiki P Menon, Kai ZinnAbstract:Background: The neuromuscular system of the Drosophila larva contains a small number of identified Motor neurons that make genetically defined synaptic connections with muscle fibers. We drove high-level expression of genes in these Motor neurons by crossing 2293 GAL4-driven EP element lines with known insertion site sequences to lines containing a pan-neuronal GAL4 source and UAS-green fluorescent protein elements. This allowed visualization of every synapse in the neuromuscular system in live larvae. Results: We identified 114 EPs that generate Axon guidance and/or synaptogenesis phenotypes in F1 EP x driver larvae. Analysis of genomic regions adjacent to these EPs defined 76 genes that exhibit neuromuscular gain-of-function phenotypes. Forty-one of these (known genes) have published mutant alleles; the other 35 (new genes) have not yet been characterized genetically. To assess the roles of the known genes, we surveyed published data on their phenotypes and expression patterns. We also examined loss-of-function mutants ourselves, identifying new guidance and synaptogenesis phenotypes for eight genes. At least three quarters of the known genes are important for nervous system development and/or function in wild-type flies. Conclusions: Known genes, new genes, and a set of previously analyzed genes with phenotypes in the Adh region display similar patterns of homology to sequences in other species and have equivalent EST representations. We infer from these results that most new genes will also have nervous system loss-of-function phenotypes. The proteins encoded by the 76 identified genes include GTPase regulators, vesicle trafficking proteins, kinases, and RNA binding proteins.
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profilin and the abl tyrosine kinase are required for Motor Axon outgrowth in the drosophila embryo
Neuron, 1999Co-Authors: Zachary P Wills, Corey S Goodman, Kai Zinn, David Van Vactor, Linsey C MarrAbstract:The ability of neuronal growth cones to be guided by extracellular cues requires intimate communication between signal transduction systems and the dynamic actin-based cytoskeleton at the leading edge. Profilin, a small, actin-binding protein, has been proposed to be a regulator of the cell motility machinery at leading edge membranes. However, its requirement in the developing nervous system has been unknown. Profilin associates with members of the Enabled family of proteins, suggesting that Profilin might link Abl function to the cytoskeleton. Here, genetic analysis in Drosophila is used to demonstrate that mutations in Profilin (chickadee) and Abl (abl) display an identical growth cone arrest phenotype for Axons of intersegmental nerve b (ISNb). Moreover, the phenotype of a double mutant suggests that these components function together to control Axonal outgrowth.
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receptor tyrosine phosphatases are required for Motor Axon guidance in the drosophila embryo
Cell, 1996Co-Authors: Chand J Desai, Joseph G Gindhart, Lawrence S B Goldstein, Kai ZinnAbstract:The receptor tyrosine phosphatases DPTP69D and DPTP99A are expressed on Motor Axons in Drosophila embryos. In mutant embryos lacking DPTP69D protein, Motor neuron growth cones stop growing before reaching their muscle targets, or follow incorrect pathways that bypass these muscles. Mutant embryos lacking DPTP99A are indistinguishable from wild type. Motor Axon defects in dptp69D dptp99A double mutant embryos, however, are much more severe than in embryos lacking only DPTP69D. Our results demonstrate that DPTP69D and DPTP99A are required for Motor Axon guidance and that they have partially redundant functions during development of the neuromuscular system.
Artur Kania - One of the best experts on this subject based on the ideXlab platform.
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Ephrin-Mediated cis-Attenuation of Eph Receptor Signaling Is Essential for Spinal Motor Axon Guidance
Neuron, 2011Co-Authors: Tzu Jen Kao, Artur KaniaAbstract:Summary Axon guidance receptors guide neuronal growth cones by binding in trans to Axon guidance ligands in the developing nervous system. Some ligands are coexpressed in cis with their receptors, raising the question of the relative contribution of cis and trans interactions to Axon guidance. Spinal Motor Axons use Eph receptors to select a limb trajectory in response to trans ephrins, while expressing ephrins in cis . We show that changes in Motor neuron ephrin expression result in trajectory selection defects mirrored by changes in growth cone sensitivity to ephrins in vitro, arguing for ephrin cis -attenuation of Eph function. Furthermore, the relative contribution of trans -signaling and cis -attenuation is influenced by the subcellular distribution of ephrins to membrane patches containing Eph receptors. Thus, growth cone ephrins are essential for Axon guidance in vivo and the balance between cis and trans modes of Axon guidance ligand-receptor interaction contributes to the diversity of Axon guidance signaling responses.
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specification of Motor Axon trajectory by ephrin b ephb signaling symmetrical control of Axonal patterning in the developing limb
Neuron, 2008Co-Authors: Victor Luria, Thomas M Jessell, Dayana Krawchuk, Ed Laufer, Artur KaniaAbstract:Summary Studies of the innervation of limb muscles by spinal Motor neurons have helped to define mechanisms by which Axons establish trajectories to their targets. Related Motor Axons select dorsal or ventral pathways at the base of the limb, raising the question of how these alternate trajectories are specified. EphA signaling has been proposed to control the dorsal trajectory of Motor Axons in conjunction with other signaling systems, although the respective contributions of each system to Motor Axon guidance are unclear. We show that the expression of EphB receptors by Motor Axons, and ephrin-B ligands by limb mesenchymal cells, directs the ventral trajectory of Motor Axons. Our findings reveal symmetry in the molecular strategies that establish this aspect of nerve-muscle connectivity. The involvement of ephrin:Eph signaling in guiding both sets of Motor Axons raises the possibility that other signaling systems function primarily to refine or modulate a core Eph signaling program.
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distinct roles for secreted semaphorin signaling in spinal Motor Axon guidance
Neuron, 2005Co-Authors: Andrea B Huber, Artur Kania, Tracy S Tran, Natalia V De Marco Garcia, Ivo Lieberam, Dontais Johnson, Thomas M Jessell, David D Ginty, Alex L KolodkinAbstract:Neuropilins, secreted semaphorin coreceptors, are expressed in discrete populations of spinal Motor neurons, suggesting they provide critical guidance information for the establishment of functional Motor circuitry. We show here that Motor Axon growth and guidance are impaired in the absence of Sema3A-Npn-1 signaling. Motor Axons enter the limb precociously, showing that Sema3A controls the timing of Motor Axon in-growth to the limb. Lateral Motor column (LMC) Motor Axons within spinal nerves are defasciculated as they grow toward the limb and converge in the plexus region. Medial and lateral LMC Motor Axons show dorso-ventral guidance defects in the forelimb. In contrast, Sema3F-Npn-2 signaling guides the Axons of a medial subset of LMC neurons to the ventral limb, but plays no major role in regulating their fasciculation. Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of Motor Axon growth and guidance during the formation of spinal Motor connections.