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Frederic Charron - One of the best experts on this subject based on the ideXlab platform.
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Nonconventional Axon Guidance cues: Hedgehog, TGF-β/BMP, and Wnts in Axon Guidance
Cellular Migration and Formation of Axons and Dendrites, 2020Co-Authors: Patricia T. Yam, Frederic CharronAbstract:Abstract During nervous system development, Axons, led by the growth cone, must navigate to their targets. Axon Guidance cues are molecules in the extracellular environment that attract or repel Axons to guide them along their correct trajectory. Nonconventional Axon Guidance cues include morphogens of the Hedgehog, TGF-β/BMP, and Wnt families. The canonical signaling pathways employed by morphogens to specify cell fate transduce a signal to the nucleus and regulate transcription. In contrast, Hedgehog, TGF-β/BMP, and Wnts guide Axons through noncanonical signaling pathways that regulate local changes in the growth cone. The signaling mechanisms of Hedgehog, TGF-β/BMP, and Wnts in Axon Guidance are transcription independent and differ from the canonical signaling pathways. Furthermore, in addition to directly guiding Axons, some nonconventional Guidance cues modulate the response of Axons to other Guidance cues, adding another level of complexity to Axon pathfinding mechanisms.
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the ciliary protein arl13b functions outside of the primary cilium in shh mediated Axon Guidance
Cell Reports, 2019Co-Authors: Julien Ferent, Tamara Caspary, Laura E Mariani, Eduardo D Gigante, Sandii Constable, Emilie Legué, Karel F Liem, Frederic CharronAbstract:Summary The small GTPase Arl13b is enriched in primary cilia and regulates Sonic hedgehog (Shh) signaling. During neural development, Shh controls patterning and proliferation through a canonical, transcription-dependent pathway that requires the primary cilium. Additionally, Shh controls Axon Guidance through a non-canonical, transcription-independent pathway whose connection to the primary cilium is unknown. Here we show that inactivation of Arl13b results in defective commissural Axon Guidance in vivo. In vitro, we demonstrate that Arl13b functions autonomously in neurons for their Shh-dependent Guidance response. We detect Arl13b protein in Axons and growth cones, far from its well-established ciliary enrichment. To test whether Arl13b plays a non-ciliary function, we used an engineered, cilia-localization-deficient Arl13b variant and found that it was sufficient to mediate Shh Axon Guidance in vitro and in vivo. Together, these results indicate that, in addition to its ciliary role in canonical Shh signaling, Arl13b plays a cilia-independent role in Shh-mediated Axon Guidance.
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Polarized Dock Activity Drives Shh-Mediated Axon Guidance.
Developmental cell, 2018Co-Authors: Shirin Makihara, Julien Ferent, Patricia T. Yam, Steves Morin, Jean-françois Côté, Frederic CharronAbstract:Summary In the developing spinal cord, Sonic hedgehog (Shh) attracts commissural Axons toward the floorplate. How Shh regulates the cytoskeletal remodeling that underlies growth cone turning is unknown. We found that Shh-mediated growth cone turning requires the activity of Docks, which are unconventional GEFs. Knockdown of Dock3 and 4, or their binding partner ELMO1 and 2, abolished commissural Axon attraction by Shh in vitro. Dock3/4 and ELMO1/2 were also required for correct commissural Axon Guidance in vivo. Polarized Dock activity was sufficient to induce Axon turning, indicating that Docks are instructive for Axon Guidance. Mechanistically, we show that Dock and ELMO interact with Boc, the Shh receptor, and that this interaction is reduced upon Shh stimulation. Furthermore, Shh stimulation translocates ELMO to the growth cone periphery and activates Rac1. This identifies Dock/ELMO as an effector complex of non-canonical Shh signaling and demonstrates the instructive role of GEFs in Axon Guidance.
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Axon Guidance: Gained in Translation.
Neuron, 2018Co-Authors: Frederic CharronAbstract:In this issue of Neuron, Cagnetta et al. (2018) describe a novel method to identify, in an unbiased manner, newly synthesized Axonal proteins in response to Axon Guidance cues. They find that Axons stimulated by different Guidance cues (Netrin-1, BDNF, and Sema3A) show distinct and common signatures.
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Nonconventional Axon Guidance Cues
Cellular Migration and Formation of Neuronal Connections, 2013Co-Authors: Luisa Izzi, Frederic CharronAbstract:Neurons connect with their targets by sending out Axons that navigate through the embryo in response to Guidance cues. In addition to classical Axon Guidance molecules, morphogens, which function in concentration gradients to promote cell fate specification and tissue patterning, also act as graded positional cues to guide the migration of Axons. This chapter focuses on the role of members of the Hedgehog, transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP), and Wnt/Wingless families in Axon pathfinding and the molecular mechanisms that underlie their Guidance function in vertebrates and invertebrates.
Esther T. Stoeckli - One of the best experts on this subject based on the ideXlab platform.
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Understanding Axon Guidance: are we nearly there yet?
Development (Cambridge England), 2018Co-Authors: Esther T. StoeckliAbstract:During nervous system development, neurons extend Axons to reach their targets and form functional circuits. The faulty assembly or disintegration of such circuits results in disorders of the nervous system. Thus, understanding the molecular mechanisms that guide Axons and lead to neural circuit formation is of interest not only to developmental neuroscientists but also for a better comprehension of neural disorders. Recent studies have demonstrated how crosstalk between different families of Guidance receptors can regulate Axonal navigation at choice points, and how changes in growth cone behaviour at intermediate targets require changes in the surface expression of receptors. These changes can be achieved by a variety of mechanisms, including transcription, translation, protein-protein interactions, and the specific trafficking of proteins and mRNAs. Here, I review these Axon Guidance mechanisms, highlighting the most recent advances in the field that challenge the textbook model of Axon Guidance.
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Where does Axon Guidance lead us
F1000Research, 2017Co-Authors: Esther T. StoeckliAbstract: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 are frequently found in genetic and genomic studies of neurodevelopmental disorders.
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Canonical wnt signaling is required for commissural Axon Guidance.
Developmental neurobiology, 2015Co-Authors: Evelyn Avilés, Esther T. StoeckliAbstract:Morphogens have been identified as Guidance cues for postcrossing commissural Axons in the spinal cord. Shh has a dual effect on postcrossing commissural Axons: a direct repellent effect mediated by Hhip as a receptor, and an indirect effect by shaping a Wnt activity gradient. Wnts were shown to be attractants for postcrossing commissural Axons in both chicken and mouse embryos. In mouse, the effects of Wnts on Axon Guidance were concluded to depend on the planar cell polarity (PCP) pathway. Canonical Wnt signaling was excluded based on the absence of Axon Guidance defects in mice lacking Lrp6 which is an obligatory coreceptor for Fzd in canonical Wnt signaling. In the loss-of-function studies reported here, we confirmed a role for the PCP pathway in postcrossing commissural Axon Guidance also in the chicken embryo. However, taking advantage of the precise temporal control of gene silencing provided by in ovo RNAi, we demonstrate that canonical Wnt signaling is also required for proper Guidance of postcrossing commissural Axons in the developing spinal cord. Thus, Axon Guidance does not seem to depend on any one of the classical Wnt signaling pathways but rather involve a network of Wnt receptors and downstream components.
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semaphorin 6b acts as a receptor in post crossing commissural Axon Guidance
Development, 2014Co-Authors: Irwin Andermatt, Nicole H. Wilson, Matthias Gesemann, Timothy Bergmann, Olivier Mauti, Shanthini Sockanathan, Esther T. StoeckliAbstract: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 navigation at the midline, whereas a cis-interaction between PlxnA2 and Sema6B on pre-crossing commissural Axons may regulate the responsiveness of Axons to floorplate-derived cues.
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Longitudinal Axon Guidance
Current opinion in neurobiology, 2006Co-Authors: Esther T. StoeckliAbstract:Our knowledge about molecular mechanisms underlying Axon Guidance along the antero-posterior axis in contrast to the dorso-ventral axis of the developing nervous system is very limited. During the past two years in vitro and in vivo studies have indicated that morphogens have a role in longitudinal Axon Guidance. Morphogens are secreted proteins that act in a concentration-dependent manner on susceptible groups of precursor cells and induce their differentiation to a specific cell fate. Thus, gradients of morphogens are responsible for the appropriate patterning of the nervous system during early phases of neural development. Therefore, it was surprising to find that gradients of two of these morphogens, Wnt4 and Shh, can be re-used for longitudinal Axon Guidance during later stages of nervous system development.
Artur Kania - One of the best experts on this subject based on the ideXlab platform.
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EphA4 receptor shedding regulates spinal motor Axon Guidance.
Current biology : CB, 2014Co-Authors: Graziana Gatto, Daniel Morales, Artur Kania, Ruediger KleinAbstract:Summary Background Proteolytic processing of Axon Guidance receptors modulates their expression and functions. Contact repulsion by membrane-associated ephrins and Eph receptors was proposed to be facilitated by ectodomain cleavage, but whether this phenomenon is required for Axon Guidance in vivo is unknown. Results In support of established models, we find that cleavage of EphA4 promotes cell-cell and growth cone-cell detachment in vitro. Unexpectedly, however, a cleavage resistant isoform of EphA4 is as effective as a wild-type EphA4 in redirecting motor Axons in limbs. Mice in which EphA4 cleavage is genetically abolished have motor Axon Guidance defects, suggesting an important role of EphA4 cleavage in nonneuronal tissues such as the limb mesenchyme target of spinal motor neurons. Indeed, we find that blocking EphA4 cleavage increases expression of full-length EphA4 in limb mesenchyme, which—via cis -attenuation—apparently reduces the effective concentration of ephrinAs capable of triggering EphA4 forward signaling in the motor Axons. Conclusions We propose that EphA4 cleavage is required to establish the concentration differential of active ephrins in the target tissue that is required for proper Axon Guidance. Our study reveals a novel mechanism to regulate Guidance decision at an intermediate target based on the modulation of ligand availability by the proteolytic processing of the receptor.
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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.
Yimin Zou - One of the best experts on this subject based on the ideXlab platform.
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Morphogens as conserved Axon Guidance cues.
Current Opinion in Neurobiology, 2007Co-Authors: Yimin Zou, Anna I LyuksyutovaAbstract:Morphogen family proteins are now widely appreciated as Axon Guidance cues. Because their roles as morphogens are highly conserved across phylogeny, their functional conservation in Axon Guidance is now being rigorously examined. Recent studies suggest that morphogens are important in shaping topographic projections in chick and Drosophila visual systems, a process that occurs even later in development.
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Wnt signaling in Axon Guidance.
Trends in Neurosciences, 2004Co-Authors: Yimin ZouAbstract:Recent studies have identified Wnt proteins as conserved Axon Guidance molecules in vertebrates and invertebrates. Wnt proteins are a large family of diffusible factors that play several important roles, both in embryonic development and in adult function. The signaling mechanisms of Wnt proteins are complex and, because Wnts are newly discovered as Axon Guidance cues, little is known about how Wnt signaling controls the direction of growth cone navigation - a process that is crucial in development of the nervous system. This review summarizes recent work on the role of Wnts in Axon Guidance and discusses the possible signaling mechanisms involved in growth cone Guidance. Understanding how Wnts regulate Axon wiring will not only help us to understand how the nervous system is connected but also provide possible tools for Axon regeneration.
Rolf O. Karlstrom - One of the best experts on this subject based on the ideXlab platform.
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belladonna/(lhx2) is required for neural patterning and midline Axon Guidance in the zebrafish forebrain
Development (Cambridge England), 2006Co-Authors: Anandita Seth, James Culverwell, Mitchell Walkowicz, Sabrina Toro, Jens M. Rick, Stephan C.f. Neuhauss, Zoltán M. Varga, Rolf O. KarlstromAbstract:Some of the earliest Axon pathways to form in the vertebrate forebrain are established as commissural and retinal Axons cross the midline of the diencephalon and telencephalon. To better understand Axon Guidance in the forebrain, we characterized the zebrafish belladonna ( bel ) mutation, which disrupts commissural and retinal Axon Guidance in the forebrain. Using a positional cloning strategy, we determined that the bel locus encodes zebrafish Lhx2, a lim-homeodomain transcription factor expressed in the brain, eye and fin buds. We show that bel(lhx2) function is required for patterning in the ventral forebrain and eye, and that loss of bel function leads to alterations in regulatory gene expression, perturbations in Axon Guidance factors, and the absence of an optic chiasm and forebrain commissures. Our analysis reveals new roles for lhx2 in midline Axon Guidance, forebrain patterning and eye morphogenesis.
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Genetic analysis of Axon Guidance and mapping in the zebrafish
Trends in neurosciences, 1997Co-Authors: Rolf O. Karlstrom, Torsten Trowe, Friedrich BonhoefferAbstract:Systematic genetic screens have been powerful tools in identifying genes responsible for Axon Guidance in fruitflies and nematodes. This approach has now been extended to the study of Axon Guidance and the formation of topographic neuronal connections in the vertebrate brain. A systematic genetic screen was used to identify genes responsible for precise Axon pathfinding and targeting in the retinotectal system of the zebrafish (Danio rerio). Over 30 genes were found that affect either: (1) retinal Axon pathfinding to the contralateral tectal lobe; or (2) the topographic connection between the eye and the tectum. The zebrafish retinotectal mutants represent a new resource for the study of Axon Guidance in the vertebrate brain.