A Spatiotemporal Sequence of Sensitization to Slits and Semaphorins Orchestrates Commissural Axon Navigation

Pignata, Aurora; Ducuing, Hugo; Boubakar, Leïla; Gardette, Thibault; Kindbeiter, Karine; Bozon, Muriel; Tauszig-Delamasure, Servane; Falk, Julien; Thoumine, Olivier; Castellani, Valérie

doi:10.1016/j.celrep.2019.08.098

Cited by 35 publications

(32 citation statements)

References 26 publications

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“…We thus electroporated pHluo-PlxnA1 WT and pHluo-PlxnA1 Y1815F in the neural tube of the chicken embryo and performed time lapse analysis of the commissural axon navigation as in Pignata et al (2019). We first plotted the trajectories of individual axons at successive time points, classifying them as straight or curved.…”

Section: Plxna1 Y1815f Expressing Axons Fail To Maintain Forward Dirementioning

confidence: 99%

“…These concentrations were selected according to our previous work in which we compared the outcome of different concentrations on the FP navigation and selected the conditions that gave the better compromise between receptor expression and ability of FP crossing. The pHluo dependency was controlled by in vitro cell line transfection as in Pignata et al, (2019).…”

Section: In Ovo Electroporation Open-book Mounting and Imagingmentioning

confidence: 99%

“…FL mouse pHluo-PlxnA1 Y1815F was obtained by directed mutagenesis using the In-fusion HD Cloning Plus Kit (638909, Ozyme) with the following primers: 5' AGG TAC TTT GCT GAC ATT GCC and 5' GTC AGC AAA GTA CCT TTC AAC. The pH dependency of the fluorescence was validated as inPignata et al (2019).Dual-taggedSlit2 was designed using the human Slit2 sequence (NM_001289135.2) and ordered from Genscript Biotech. Briefly, Cerulean was inserted after Slit2 signal peptide (MRGVGWQMLSLGLVLAILNKVAPQACPA) and Slit2 FL sequence.…”

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confidence: 99%

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Iterative inhibition of commissural growth cone exploration, not post-crossing barrier, ensures forward midline navigation through SlitC-PlxnA1 signaling

Ducuing

Gardette

Pignata

et al. 2020

Preprint

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Sensitization to Slits and Semaphorin (Sema)3B floor plate repellents after midline crossing is thought to be the mechanism expelling commissural axons contralaterally and preventing their back-turning. We studied the role of Slit-C terminal fragment sharing with Sema3B the Plexin (Plxn) A1 receptor, newly implicated in midline guidance. We generated a knock-in mouse strain baring PlxnA1Y1815F mutation altering SlitC but not Sema3B responses and observed recrossing phenotypes. Using fluorescent reporters, we found that Slits and Sema3B form clusters decorating an unexpectedly complex mesh of ramified FP glia basal processes spanning the entire navigation path. Time-lapse analyzes revealed that impaired SlitC sensitivity destabilized axon trajectories by inducing high levels of growth cone exploration from the floor plate entry, increasing risk of aberrant decisions. Thus, FP crossing is unlikely driven by post-crossing sensitization to SlitC. Rather, SlitC limits growth cone plasticity and exploration through reiterated contacts, continuously imposing a straight and forward-directed trajectory.

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Section: Plxna1 Y1815f Expressing Axons Fail To Maintain Forward Dirementioning

confidence: 99%

Section: In Ovo Electroporation Open-book Mounting and Imagingmentioning

confidence: 99%

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confidence: 99%

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Iterative inhibition of commissural growth cone exploration, not post-crossing barrier, ensures forward midline navigation through SlitC-PlxnA1 signaling

Ducuing

Gardette

Pignata

et al. 2020

Preprint

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“…SO and SR correspond to layers where axons from CA3 and CA2 PNs synapse onto dendrites CA1 PNs, while the apical tuft of CA1 PNs in SLM receives long-range inputs from the entorhinal cortex (EC). To gain more insights into the postsynaptic localization of Robo2 at excitatory synapses received by PNs, we used ex utero electroporation to express a pHluorin-tagged version of Robo2 in pyramidal neurons in vitro 12 . A pHluorin tag fused to the extracellular domain of Robo2 allows the specific visualization of the plasma membrane targeted form of Robo2, but not the pool of the protein contained in intracellular vesicles 13 .…”

Section: Robo2 Is Expressed In the Developing And Mature Hippocampus mentioning

confidence: 99%

Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

Blockus

Rolotti

Szoboszlay

et al. 2019

Preprint

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The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via itsIg4-5 domains. In vivo 2-photon Ca 2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.Proper circuit function relies on the establishment of synaptic connections characterized by a high degree of cell type and subcellular specificity. How this striking degree of synaptic specificity is achieved during development remains poorly understood, especially in the complex brains of mammals. Many cell surface molecules that mediate molecular recognition between axons and dendrites during circuit development have been identified 1-4 . These trans-synaptic adhesion molecules are often expressed in a cell-type specific manner 5 thereby determining the pool of a cell's possible synaptic partners. Some classes of these molecules have synaptic organizing properties evidenced by their direct or indirect ability to recruit key pre-and postsynaptic proteins. When axons reach their target areas, a cellular switch from a phase of growth and branching to synaptogenesis is observed. This switch is characterized by dynamic instability of adhesion progressively leading to more stable patterns of synaptic connectivity characterizing adult circuits. One of the foremost outstanding questions in neuroscience is how synapse formation is mechanistically integrated with earlier developmental steps such as axon guidance 3 and branching. One potential mechanism for coordinating this transition relies on the possibility that axon guidance cues acquire synaptogenic functions during circuit wiring. Indeed, evidence for such dual use of developmental molecules has been reported 6 . However, it remains unclear what prompts molecules to switch their function from axon guidance to synaptogenesis.Here we report that the well-studied axon guidance ligand-receptor pair Sl...

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“…In addition to the temporal control of axon outgrowth, the temporal regulation of receptor availability at the surface of axons is critical in determining the sensitivity of axons to signals presented by other axons. It also allows axons to change their responsiveness to a cue in a precise spatial and temporal manner [ 11 , 38 ]. While homotypic and heterotypic interactions between axons have been recognized as essential for proper neuronal connectivity for more than four decades, our understanding of the cellular and molecular mechanisms at play has only more recently progressed.…”

Section: Introductionmentioning

confidence: 99%

Trans-Axonal Signaling in Neural Circuit Wiring

Spead

Poulain

2020

IJMS

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The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation.

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A Spatiotemporal Sequence of Sensitization to Slits and Semaphorins Orchestrates Commissural Axon Navigation

Cited by 35 publications

References 26 publications

Iterative inhibition of commissural growth cone exploration, not post-crossing barrier, ensures forward midline navigation through SlitC-PlxnA1 signaling

Iterative inhibition of commissural growth cone exploration, not post-crossing barrier, ensures forward midline navigation through SlitC-PlxnA1 signaling

Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

Trans-Axonal Signaling in Neural Circuit Wiring

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