Papers by Esther Stoeckli
isoforms, called 2a and 2b, show only 10% identity in
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Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for... more Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for plexins and neuropilins. Although class-6 semaphorins are transmembrane proteins, they have been implicated as ligands in different aspects of neural development, including neural crest cell migration, axon guidance and cerebellar development. However, the specific spatial and temporal expression of semaphorin 6B (Sema6B) in chick commissural neurons suggested a receptor role in axon guidance at the spinal cord midline. Indeed, in the absence of Sema6B, post-crossing commissural axons lacked an instructive signal directing them rostrally along the contralateral floorplate border, resulting in stalling at the exit site or even caudal turns. Truncated Sema6B lacking the intracellular domain was unable to rescue the loss-of-function phenotype, confirming a receptor function of Sema6B. In support of this, we demonstrate that Sema6B binds to floorplate-derived plexin A2 (PlxnA2) for navigati...
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Loss-of-function approaches are important tools for functional gene analysis. Due to the availabi... more Loss-of-function approaches are important tools for functional gene analysis. Due to the availability of sophisticated methods to manipulate gene expression in embryonic stem cells that can be used to generate mutant mice, the mouse is by far the most important vertebrate model organism for basic and applied biomedical research. Unfortunately, the available methods do not allow for precise temporal and spatial control of gene silencing during embryonic development limiting the usefulness of the mouse for developmental studies. Due to their easy accessibility chicken embryos have been one of the preferred model organisms for developmental studies. Their disadvantage, the lack of genetic tools, could be overcome by the development of in ovo RNAi (in ovo RNA interference), a method that allows for temporal and spatial control of gene silencing in vivo.
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eLife
Axon navigation depends on the interactions between guidance molecules along the trajectory and s... more Axon navigation depends on the interactions between guidance molecules along the trajectory and specific receptors on the growth cone. However, our in vitro and in vivo studies on the role of Endoglycan demonstrate that in addition to specific guidance cue – receptor interactions, axon guidance depends on fine-tuning of cell-cell adhesion. Endoglycan, a sialomucin, plays a role in axon guidance in the central nervous system of chicken embryos, but it is neither an axon guidance cue nor a receptor. Rather, Endoglycan acts as a negative regulator of molecular interactions based on evidence from in vitro experiments demonstrating reduced adhesion of growth cones. In the absence of Endoglycan, commissural axons fail to properly navigate the midline of the spinal cord. Taken together, our in vivo and in vitro results support the hypothesis that Endoglycan acts as a negative regulator of cell-cell adhesion in commissural axon guidance.
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ABSTRACTDuring neural circuit formation, axons navigate several choice points to reach their fina... more ABSTRACTDuring neural circuit formation, axons navigate several choice points to reach their final target. At each one of these intermediate targets, growth cones need to switch responsiveness from attraction to repulsion in order to move on. Molecular mechanisms that allow for the precise timing of surface expression of a new set of receptors that support the switch in responsiveness are difficult to study in vivo. Mostly, mechanisms are inferred from the observation of snapshots of many different growth cones analyzed in different preparations of tissue harvested at distinct time points. However, to really understand the behavior of growth cones at choice points, a single growth cone should be followed arriving at and leaving the intermediate target.Here, we describe a spinal cord preparation that allows for live imaging of individual axons during navigation in their intact environment. The possibility to observe single growth cones navigating their intermediate target allows for ...
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PLoS genetics, 2018
Axonal growth and guidance rely on correct growth cone responses to guidance cues. Unlike the sig... more Axonal growth and guidance rely on correct growth cone responses to guidance cues. Unlike the signaling cascades that link axonal growth to cytoskeletal dynamics, little is known about the crosstalk mechanisms between guidance and membrane dynamics and turnover. Recent studies indicate that whereas axonal attraction requires exocytosis, chemorepulsion relies on endocytosis. Indeed, our own studies have shown that Netrin-1/Deleted in Colorectal Cancer (DCC) signaling triggers exocytosis through the SNARE Syntaxin-1 (STX1). However, limited in vivo evidence is available about the role of SNARE proteins in axonal guidance. To address this issue, here we systematically deleted SNARE genes in three species. We show that loss-of-function of STX1 results in pre- and post-commissural axonal guidance defects in the midline of fly, chick, and mouse embryos. Inactivation of VAMP2, Ti-VAMP, and SNAP25 led to additional abnormalities in axonal guidance. We also confirmed that STX1 loss-of-functi...
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F1000Research, 2017
During neural circuit formation, axons need to navigate to their target cells in a complex, const... more During neural circuit formation, axons need to navigate to their target cells in a complex, constantly changing environment. Although we most likely have identified most axon guidance cues and their receptors, we still cannot explain the molecular background of pathfinding for any subpopulation of axons. We lack mechanistic insight into the regulation of interactions between guidance receptors and their ligands. Recent developments in the field of axon guidance suggest that the regulation of surface expression of guidance receptors comprises transcriptional, translational, and post-translational mechanisms, such as trafficking of vesicles with specific cargos, protein-protein interactions, and specific proteolysis of guidance receptors. Not only axon guidance molecules but also the regulatory mechanisms that control their spatial and temporal expression are involved in synaptogenesis and synaptic plasticity. Therefore, it is not surprising that genes associated with axon guidance ar...
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Developmental Biology, 2016
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Development, 2016
Axon guidance at choice points depends on the precise regulation of guidance receptors on the gro... more Axon guidance at choice points depends on the precise regulation of guidance receptors on the growth cone surface. Upon arrival at the intermediate target or choice point, a switch from attraction to repulsion is required for the axon to move on. Dorsal commissural (dI1) axons crossing the ventral midline of the spinal cord in the floor plate represent a convenient model for the analysis of the molecular mechanism underlying the switch in axonal behavior. We identified a role of Calsyntenin1 in the regulation of vesicular trafficking of guidance receptors in dI1 axons at choice points. In cooperation with RabGDI, Calsyntenin1 shuttles Rab11-positive vesicles containing Robo1 to the growth cone surface in a precisely regulated manner. In contrast, Calsyntenin1-mediated trafficking of Frizzled3, a guidance receptor in the Wnt pathway, is independent of RabGDI. Thus, tightly regulated insertion of guidance receptors, which is required for midline crossing and the subsequent turn into t...
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<b>Copyright information:</b>Taken from "Semaphorin6A acts as a gate keeper betw... more <b>Copyright information:</b>Taken from "Semaphorin6A acts as a gate keeper between the central and the peripheral nervous system"http://www.neuraldevelopment.com/content/2/1/28Neural Development 2007;2():28-28.Published online 18 Dec 2007PMCID:PMC2238753. In the absence of Sema6A from BCCs, motoneurons stream out of the ventral spinal cord and migrate along the ventral roots (arrows). The open arrow points to a motoneuron that is located in the ventral funiculus. In control-treated embryos motoneurons along ventral roots or in the ventral funiculus were rarely seen. Motoneurons were identified by Isl-1 (red). An EGFP plasmid was co-injected with the dsRNA derived from SEMA6A. Axons were stained with an antibody against neurofilament (blue). Note that sensory neurons in the DRG (asterisk in (a, b)) are also stained by Isl-1. Perturbation of Sema6B or Sema6D did not enhance the number of motoneurons in the periphery compared to control-treated embryos injected only with the plasmid encoding EGFP. Three asterisks indicate &lt; 0.0001 for the comparison between dsS6A and all other treatment groups. Values are given as mean ± standard error of mean. Bar: 50 μm.
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Frontiers in cellular neuroscience, 2013
As indicated by their name, morphogens were first identified for their role in the formation of t... more As indicated by their name, morphogens were first identified for their role in the formation of tissues early in development. Secreted from a source, they spread through the tissue to form gradients by which they affect the differentiation of precursor cells in a concentration-dependent manner. In this context, the antagonistic roles of the morphogens of the Wnt family and Sonic hedgehog (Shh) in the specification of cell types along the dorso-ventral axis of the neural tube have been studied in detail. However, more recently, morphogens have been demonstrated to act well beyond the early stages of nervous system development, as additional roles of morphogen gradients in vertebrate neural circuit formation have been identified. Both Wnt and Shh affect neural circuit formation at several stages by their influence on neurite extension, axon pathfinding and synapse formation. In this review, we will summarize the mechanisms of morphogen function during axon guidance in the vertebrate n...
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Development, 2014
Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for... more Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for plexins and neuropilins. Although class-6 semaphorins are transmembrane proteins, they have been implicated as ligands in different aspects of neural development, including neural crest cell migration, axon guidance and cerebellar development. However, the specific spatial and temporal expression of semaphorin 6B (Sema6B) in chick commissural neurons suggested a receptor role in axon guidance at the spinal cord midline. Indeed, in the absence of Sema6B, post-crossing commissural axons lacked an instructive signal directing them rostrally along the contralateral floorplate border, resulting in stalling at the exit site or even caudal turns. Truncated Sema6B lacking the intracellular domain was unable to rescue the loss-of-function phenotype, confirming a receptor function of Sema6B. In support of this, we demonstrate that Sema6B binds to floorplate-derived plexin A2 (PlxnA2) for navigati...
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Oligonucleotides, 2003
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Nucleic Acids Research, 2011
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Neuron, 2013
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Neural Development, 2008
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Neural Development, 2012
Background Axons navigate to their future synaptic targets with the help of choice points, interm... more Background Axons navigate to their future synaptic targets with the help of choice points, intermediate targets that express axon guidance cues. Once they reach a choice point, axons need to switch their response from attraction to repulsion in order to move on with the next stage of their journey. The mechanisms underlying the change in axonal responsiveness are poorly understood. Commissural axons become sensitive to the repulsive activity of Slits when they cross the ventral midline of the CNS. Responsiveness to Slits depends on surface expression of Robo receptors. In Drosophila, Commissureless (Comm) plays a crucial regulatory role in midline crossing by keeping Robo levels low on precommissural axons. Interestingly, to date no vertebrate homolog of comm has been identified. Robo3/Rig1 has been shown to control Slit sensitivity before the midline, but without affecting Robo1 surface expression. Results We had identified RabGDI, a gene linked to human mental retardation and an e...
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Development, 2010
The Necl/SynCAM subgroup of immunoglobulin superfamily cell adhesion molecules has been implicate... more The Necl/SynCAM subgroup of immunoglobulin superfamily cell adhesion molecules has been implicated in late stages of neural circuit formation. They were shown to be sufficient for synaptogenesis by their trans-synaptic interactions. Additionally, they are involved in myelination, both in the central and the peripheral nervous system, by mediating adhesion between glia cells and axons. Here, we show that Necls/SynCAMs are also required for early stages of neural circuit formation. We demonstrate a role for Necls/SynCAMs in post-crossing commissural axon guidance in the developing spinal cord in vivo. Necl3/SynCAM2, the family member that has not been characterized functionally so far, plays a crucial role in this process. It is expressed by floorplate cells and interacts with Necls/SynCAMs expressed by commissural axons to mediate a turning response in post-crossing commissural axons.
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Current Opinion in Neurobiology, 2006
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Papers by Esther Stoeckli