Axon guidance at the spinal cord midline—A live imaging perspective

Dumoulin, Alexandre; Zuñiga, Nikole R.; Stoeckli, Esther T.

doi:10.1002/cne.25107

Cited by 16 publications

(26 citation statements)

References 54 publications

(84 reference statements)

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“…During the second phase of medulla targeting, we showed Notch OFF DCN axons amplify into several long parallel actin-rich fibres generated from single cells. The formation of such axonal structures is not restricted to the DCN 27,[29][30][31] . Mouse retinal ganglion cell axons display similar elongated growth cone (40µm) when navigating along the optic nerve 31 .…”

Section: Discussionmentioning

confidence: 99%

Probabilistic axon targeting dynamics lead to individualized brain wiring

Andriatsilavo

Dumoulin

Dutta

et al. 2022

Preprint

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Developmental variation in brain-wiring contributes to behavioural individuality1,2. However, how and when individualized wiring diagrams emerge and become stable during development remains largely unknown. Here, we explored axon targeting dynamics in individual brains using live-imaging of a developing Drosophila visual circuit and discovered that targeting choice is an algorithmic multi-step growth process with variable outcomes. Using optogenetics, we found that temporally restricted Notch lateral-inhibition defines a subset of neurons with a probabilistic potential to innervate distal targets. Next, axons from NotchOFF neurons amplify into long actin-rich multi-fibre structures necessary for distal growth. A subset of these NotchOFF neurons create distal targeting axons by stabilizing microtubule growth in one of their actin fibres. Amplified axons without tubulin-stabilized fibres retract, resulting in the stochastic selection of a different number of distal targeting axons in each brain. Pharmacological microtubule destabilization suffices to inhibit this targeting. We observed a similar axonal amplification-stabilization process in the developing chick spinal cord, suggesting a conserved mechanism. Finally, early microtubule patterns predict the adult brain- wiring of an individual in a target-independent manner prior to synapse formation3,4. Thus, we show that a temporal succession of genetically encoded stochastic processes explains the emergence of individual wiring variation.

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Section: Discussionmentioning

confidence: 99%

Probabilistic axon targeting dynamics lead to individualized brain wiring

Andriatsilavo

Dumoulin

Dutta

et al. 2022

Preprint

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“…Ex vivo live imaging recordings were performed as previously described ( Dumoulin et al, 2021 ). Shortly, to observe commissural axon navigation in live imaging experiments, E3 (HH17-18) chicken embryos were injected and electroporated unilaterally with the Math1::tdTomato-F plasmid (700 ng/µl) in ovo .…”

Section: Methodsmentioning

confidence: 99%

“…Quantifications and video montages were done using Fiji/ImageJ ( Schindelin et al, 2012 ). Kymographic analysis was performed as previously described ( Dumoulin et al, 2021 ) using Fiji/ImageJ in a ROI (126 × 75 µm) within the floorplate representing the movement ( x axis) of dI1 axons crossing the floorplate over time (24 h, y axis).…”

Section: Methodsmentioning

confidence: 99%

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

Vaccaro

Dumoulin²,

Zuñiga³

et al. 2022

J. Neurosci.

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Nogo-66 receptors (NgR1-3) are glycosylphosphatidyl inositol-linked proteins that belong to the leucine-rich repeat superfamily. Through binding to myelin-associated inhibitors, NgRs contribute to the inhibition of axonal regeneration after spinal cord injury. Their role in limiting synaptic plasticity and axonal outgrowth in the adult CNS has been described previously, but not much is known about their role during the development of the nervous system. Here, we show that NgR1 and NgR3 mRNAs are expressed during spinal cord development of the chicken embryo. In particular, they are expressed in the dI1 subpopulation of commissural neurons during the time when their axons navigate toward and across the floorplate, the ventral midline of the spinal cord. To assess a potential role of NgR1 and NgR3 in axon guidance, we downregulated them using in ovo RNAi and analyzed the trajectory of commissural axons by tracing them in open-book preparations of spinal cords. Our results show that loss of either NgR1 or NgR3 causes axons to stall in the midline area and to interfere with the rostral turn of postcrossing axons. In addition, we also show that NgR1, but not NgR3, requires neuronal PlexinA2 for the regulation of commissural axon guidance. SIGNIFICANCE STATEMENT Over the last decades, many studies have focused on the role of NgRs, particularly NgR1, in axonal regeneration in the injured adult CNS. Here, we show a physiological role of NgRs in guiding commissural axons during early development of the chicken spinal cord in vivo . Both NgR1 and NgR3 are required for midline crossing and subsequent turning of postcrossing axons into the longitudinal axis of the spinal cord. NgR1, but not NgR3, forms a receptor complex with PlexinA2 during axon guidance. Overall, these findings provide a link between neural regenerative mechanisms and developmental processes.

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“…As a result, floor-plate cells were “torn out” of the floor plate and dislocated into the commissure beneath the floor plate. In an ex vivo preparation for live imaging of commissural axon navigation ( Dumoulin et al, 2021 ), the growth speed was decreased due to too much adhesion, most likely contributing to the pathfinding errors observed at the floor-plate exit site ( Baeriswyl et al, 2021 ). Too much Endoglycan also perturbed the correct navigation of the floor-plate area by commissural axons, in agreement with the idea that adhesive strength needs to be set within a certain range.…”

Section: Introductionmentioning

confidence: 99%

Endoglycan Regulates Purkinje Cell Migration by Balancing Cell-Cell Adhesion

et al. 2022

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The importance of cell adhesion molecules for the development of the nervous system has been recognized many decades ago. Functional in vitro and in vivo studies demonstrated a role of cell adhesion molecules in cell migration, axon growth and guidance, as well as synaptogenesis. Clearly, cell adhesion molecules have to be more than static glue making cells stick together. During axon guidance, cell adhesion molecules have been shown to act as pathway selectors but also as a means to prevent axons going astray by bundling or fasciculating axons. We identified Endoglycan as a negative regulator of cell-cell adhesion during commissural axon guidance across the midline. The presence of Endoglycan allowed commissural growth cones to smoothly navigate the floor-plate area. In the absence of Endoglycan, axons failed to exit the floor plate and turn rostrally. These observations are in line with the idea of Endoglycan acting as a lubricant, as its presence was important, but it did not matter whether Endoglycan was provided by the growth cone or the floor-plate cells. Here, we expand on these observations by demonstrating a role of Endoglycan during cell migration. In the developing cerebellum, Endoglycan was expressed by Purkinje cells during their migration from the ventricular zone to the periphery. In the absence of Endoglycan, Purkinje cells failed to migrate and, as a consequence, cerebellar morphology was strongly affected. Cerebellar folds failed to form and grow, consistent with earlier observations on a role of Purkinje cells as Shh deliverers to trigger granule cell proliferation.

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Axon guidance at the spinal cord midline—A live imaging perspective

Cited by 16 publications

References 54 publications

Probabilistic axon targeting dynamics lead to individualized brain wiring

Probabilistic axon targeting dynamics lead to individualized brain wiring

The Nogo-66 Receptors NgR1 and NgR3 Are Required for Commissural Axon Pathfinding

Endoglycan Regulates Purkinje Cell Migration by Balancing Cell-Cell Adhesion

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