Dynamic responses of <i>Xenopus</i> retinal ganglion cell axon growth cones to netrin‐1 as they innervate their <i>in vivo</i> target

Shirkey, Nicole J.; Manitt, Colleen; Zúñiga, Liliana Serrano; Cohen-Cory, Susana

doi:10.1002/dneu.20967

Cited by 12 publications

(22 citation statements)

References 54 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the developing Xenopus visual system, RGC axons at their target express DCC and differentially respond to netrin-1 depending on their maturational state by halting growth cone advancement within the target [ 12 ] or by rapidly increasing the number of green fluorescent protein (GFP)-tagged presynaptic specializations and subsequently increasing branch number [ 11 ]. To further characterize the roles of netrin-1 during visual circuit development, we examined the expression of netrin-1 and its receptors DCC and UNC-5 in the optic tectum at the time when tectal neurons differentiate and form connections with branching RGC axons (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the vertebrate visual system, netrin guides retinal ganglion cell (RGC) axons along the visual pathway [ 9 ]. In vitro and in vivo studies in Xenopus embryos further show that RGC axons exhibit differential responses to netrin-1 that depend on their location along the pathway and on their maturational stage [ 10 – 12 ]. At younger developmental stages, when RGC axons first reach their target, netrin-1 halts growth cone advancement and induces back branching [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro and in vivo studies in Xenopus embryos further show that RGC axons exhibit differential responses to netrin-1 that depend on their location along the pathway and on their maturational stage [ 10 – 12 ]. At younger developmental stages, when RGC axons first reach their target, netrin-1 halts growth cone advancement and induces back branching [ 12 ]. In contrast, netrin affects mature RGC axons that actively arborize within the target by promoting axonal maturation in a DCC-dependent manner by increasing presynaptic differentiation and dynamic branching [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo

et al. 2015

Self Cite

View full text Add to dashboard Cite

BackgroundNetrins are a family of extracellular proteins that function as chemotropic guidance cues for migrating cells and axons during neural development. In the visual system, netrin-1 has been shown to play a key role in retinal ganglion cell (RGC) axon growth and branching at the target, where presynaptic RGC axons form partnerships with the dendrites of tectal neurons. However, the signals that guide the connections between RGC axons and their postsynaptic partners are yet unknown. Here, we explored dynamic cellular mechanisms by which netrin-1 influences visual circuit formation, particularly those that impact postsynaptic neuronal morphology and connectivity during retinotectal wiring.ResultsTime-lapse in vivo imaging of individual Xenopus laevis optic tectal neurons co-expressing tdTomato and PSD95-GFP revealed rapid remodeling and reorganization of dendritic arbors following acute manipulations in netrin-1 levels. Effects of altered netrin signaling on developing dendritic arbors of tectal neurons were distinct from its effects on presynaptic RGC axons. Within 4 h of treatment, tectal injection of recombinant netrin-1 or sequestration of endogenous netrin with an UNC-5 receptor ectodomain induced significant changes in the directionality and orientation of dendrite growth and in the maintenance of already established dendrites, demonstrating that relative levels of netrin are important for these functions. In contrast, altering DCC-mediated netrin signaling with function-blocking antibodies induced postsynaptic specialization remodeling and changed growth directionality of already established dendrites. Reducing netrin signaling also decreased avoidance behavior in a visually guided task, suggesting that netrin is essential for emergent visual system function.ConclusionsThese in vivo findings together with the patterns of expression of netrin and its receptors reveal an important role for netrin in the early growth and guidance of vertebrate central neuron dendritic arbors. Collectively, our studies indicate that netrin shapes both pre- and postsynaptic arbor morphology directly and in multiple ways at stages critical for functional visual system development.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Following up the initial observations of growth cones in fixed tissue, it has become possible to trace living growth cones in action. In addition to the Holt Lab, the Cohen-Cory and Cline labs have also made significant contributions by characterizing the dynamics of retinal axon innervation and synapse formation in the tectum of Xenopus tadpoles in vivo [29]-[32]. Harris et al recorded the motility of growth cones along the optic tract in the living brain and characterized initial and final growth cone advance rates, branching, pausing and retracting behaviors [33].…”

Section: Use Of the Xenopus Laevis Retinotectal Pathway To Study Amentioning

confidence: 99%

Using Xenopus laevis retinal and spinal neurons to study mechanisms of axon guidance in vivo and in vitro

Erdoğan

Ebbert

Lowery

2016

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

The intricate and precise establishment of neuronal connections in the developing nervous system relies on accurate navigation of growing axons. Since Ramón y Cajal's discovery of the growth cone, the phenomenon of axon guidance has been revealed as a coordinated operation of guidance molecules, receptors, secondary messengers, and responses driven by the dynamic cytoskeleton within the growth cone. With the advent of new and accelerating techniques, Xenopus laevis emerged as a robust model to investigate neuronal circuit formation during development. We present here the advantages of the Xenopus nervous system to our growing understanding of axon guidance.

show abstract

“…Axon guidance cues are candidates that could act on both existing branches or on branch initiation. Molecules like slits, semaphorins and netrins have context-dependent promotion or suppression of branches [18,24,59,304] and at least one slit protein already helps guide RGC axons to the correct tectal layer [363].…”

Section: Branch Creationmentioning

confidence: 99%

In vivo imaging of the zebrafish retinotectal map

Kita¹

View full text Add to dashboard Cite

The precise neural connections that form during development support the creation of a functioning nervous system. An accessible experimental model for this process is the retinotectal system in zebrafish, which develops rapidly and can be observed in vivo throughout its establishment using confocal time-lapse imaging. The retinotectal connection is topographic, such that the spatial relationships of the retinal ganglion cell (RGC) somas in the retina are maintained by the arborization locations of their axons on the tectum. However, how axons find their correct arborization location on this topographic map is still debated. While initial studies suggested that zebrafish RGCs were guided directly by a growth cone to their target on the map, recent observations challenge that claim. My work characterizes a novel guidance pattern for RGCs pathfinding on the tectum. Once pathfinding through the tectal neuropil, zebrafish RGCs continually add and remove branches. The directionality of the branches is biased, in that more are pointing towards the eventual arborization zone than away from it. Growth cones, which tip some of the branches, extend mostly in straight lines rather than progressing through turns towards the target. The distance to the target is decreased by the axon branching in many directions, and selecting a branch that decreases the distance to support further rounds of branching. The mechanism of biased branching could be based on known types of input that guide connectivity during development and we focused on the contributions of activity and molecular guidance cue gradients.We hypothesized that silencing neural activity using TTX could alter the navigation methods used, but many of the characteristics of axon pathfinding were similar despite global silencing. The area covered by the branches during pathfinding decreases when the retinotectal system is electrically silent, but the biased branch ratio remains. Several measures of the arbors after the target is reached show differing patterns without activity, supporting previous evidence that activity is an important regulation of arborization dynamics.Molecularly, the retinotectal map is established through gradients of guidance cues that guide axons to their target location, cause them to stop advancing, and elaborate a terminal arbor. Through morpholino knock down we observe the different effects that two of these guidance proteins, ephrin-A5b and ephrin-A2, have on individual axons as they navigate.iii Overall, knockdown of ephrin-A5b tends to increase length, area and number of branches, while the knockdown of ephrin-A2 has the opposite effect on these measures. Additionally, a subset of axons show phenotypes that are masked by the grouped data, where several form loops instead of travelling in rather straight trajectories, or alternatively, grow long and remain relatively branchless as they travel towards the caudal extent of the tectum.The following thesis gives quantitative, detailed insight into some of the ways that activity and molec...

show abstract

Dynamic responses of Xenopus retinal ganglion cell axon growth cones to netrin‐1 as they innervate their in vivo target

Cited by 12 publications

References 54 publications

Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo

Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo

Using Xenopus laevis retinal and spinal neurons to study mechanisms of axon guidance in vivo and in vitro

In vivo imaging of the zebrafish retinotectal map

Contact Info

Product

Resources

About