Topographic-Specific Axon Branching Controlled by Ephrin-As Is the Critical Event in Retinotectal Map Development

Yates, Paul; Roskies, Adina L.; McLaughlin, Todd; O’Leary, Dennis D.M.

doi:10.1523/jneurosci.21-21-08548.2001

Cited by 191 publications

(229 citation statements)

References 48 publications

Supporting

Mentioning

222

Contrasting

Order By: Relevance

“…Thus far, it has been difficult to demonstrate ephrin-A5 in back branching and arborization in vivo (10,11), although in vitro studies have suggested a role for ephrin-A family members (12). We tested a specific role of ephrin-A5 in limiting arborization in vivo by performing CALI of ephrin-A5 with late E12 embryos, the stage when arborization in deeper layers begins (23) but before activity-dependent refinement (13).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that topographic-specific arborization is the critical event in forming the retinotopic map (12). Genetic deletion studies demonstrated that ephrin-A2 and ephrin-A5 restrict initial axon outgrowth (9), but analyses of topographically specific arborization caused by changes of ephrin-A gradients in vivo had not been performed because of lack of appropriate approaches.…”

Section: Discussionmentioning

confidence: 99%

“…Initial axon outgrowth is relatively inaccurate, and axons often overshoot beyond their correct termination zone (TZ). Topographically specific branching and arborization in higher vertebrates leads to the initial formation of the map (4) and is thought to be the critical event in map formation (12). Later remodeling by elimination of aberrant arbors refines this map by activitydependent processes (13).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ephrin-A5 restricts topographically specific arborization in the chick retinotectal projection in vivo

Sakurai

Wong

Drescher

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The retinotectal map is the best characterized model system to study how axons respond to guidance cues during the formation of the nervous system. Recent studies have shown that the critical event in forming this map is topographic-specific axon branching. To elucidate the in vivo role of the repulsive cue ephrin-A5 in this event, we used chromophore-assisted laser inactivation (CALI) to generate acute loss of ephrin-A5 function in localized areas of the posterior tectum of chick embryos in ovo and analyzed the resulting changes of retinal projections during initial outgrowth (E11) and when retinal axons arborize in the deep layers in the tectum (E12). We confirmed that ephrin-A5 functions to restrict initial axon outgrowth at E11. At E12, CALI of ephrin-A5 did not affect the extent of axon outgrowth on the tectal surface but instead caused ectopic arborization posterior to the topographically correct site in deeper layers of the tectum. This shows that ephrin-A5 restricts arborization during this critical process for developing the retinotopic map. CALI provides an approach to inactivate in vivo function in higher vertebrates with high temporal and spatial specificity that may have wide application.T he retinotectal projection is a well established model system to study mechanisms that form the topographic map of neural connections in the brain. It is thought that molecules expressed in gradients guide axons to their precise topographic targets. This chemoaffinity hypothesis proposed by Sperry (1) has been supported by the identification of molecular cues expressed in gradients in the retina and in the tectum (2). One important guidance cue is ephrin-A5 (3). The graded expression of ephrin-A ligands in the tectum coupled with expression of the Eph receptors that bind these ligands in retinal axons provides a potential molecular mechanism for defining the anteriorposterior (A-P) map (3, 4). Ephrin-A5 (5) is predominantly expressed in the posterior half of the chick tectum in a steep gradient, whereas a second ephrin, ephrin-A2 (6), is expressed in a shallower gradient across the entire tectum (7), and both gradients exist throughout the formation of the retinotectal map. These expression patterns suggest that ephrin-A5 and ephrin-A2 act in the graded repulsion of retinal axons involved in mapping. This notion is supported by aberrant retinal axon extension beyond their target areas observed in embryos with single and double deletions of the ephrin-A5 and ephrin-A2 genes (8, 9). These genetic deletion studies showed the overall importance of ephrin-A ligands as topographic labels, but how these ligands act in vivo has not been demonstrated.In mammals and avians, the development of topographical order occurs through a multistep process: initial axon outgrowth, topographically specific arborization, and remodeling (10, 11). Initial axon outgrowth is relatively inaccurate, and axons often overshoot beyond their correct termination zone (TZ). Topographically specific branching and arborization in higher vertebrates ...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Ephrin-A5 restricts topographically specific arborization in the chick retinotectal projection in vivo

Sakurai

Wong

Drescher

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The stripe assay was also applied to investigate neurite outgrowth and guidance behavior related to neuronal regeneration [12][13][14][15] and branch formation 16 . Furthermore, the stripe assay has proven valuable in dissecting signaling cascades initiated downstream of axonal guidance receptors activated by ligands printed in a striped pattern [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Stripe assay to examine axonal guidance and cell migration

et al. 2007

View full text Add to dashboard Cite

Stripe assays have been widely employed as in vitro test systems to study the responses of growing axons, as well as migrating cells, to established or novel guidance molecules. We provide detailed protocols for both the original and the modified version of this assay, as they allow the analysis of the 'guidance properties' of active components present in crude membrane fractions or as purified molecules. Silicon matrices are used to produce striped patterns of active molecules on a surface (referred to as 'carpet'), followed by culturing of neurons, or any other cell type, on these carpets. After 1-2 days in culture, striped outgrowth of extending neuritesindicative of guided migration of cell processes-can be observed. We also discuss potential other applications (e.g., in neuronal regeneration and development) and modifications of the assay. The preparation of 10-12 carpets takes approximately 4-5 h. INTRODUCTIONThe stripe assay was originally designed by F. Bonhoeffer and co-workers 1,2 in the late 1980s to analyze fundamental axonal guidance mechanisms governing the formation of the topographic map established in the chick retino-tectal system (for review, see ref.3). Employing this assay, the presence of a graded distribution of repulsive axon guidance cues, present predominantly in posterior tectal membranes, was discovered. Subsequently, this assay was modified, permitting the identification of ephrin-As as the key components present in posterior membranes that are responsible for the repulsive properties 4-7 .The stripe assay has since been used to uncover guidance cues and mechanisms in many principal neuronal projections, including, for example, the hippocampal, thalamic and olfactory systems [8][9][10][11] . The stripe assay was also applied to investigate neurite outgrowth and guidance behavior related to neuronal regeneration 12-15 and branch formation 16 . Furthermore, the stripe assay has proven valuable in dissecting signaling cascades initiated downstream of axonal guidance receptors activated by ligands printed in a striped pattern [12][13][14][15] . In addition, the guidance properties of membrane-tethered molecules as well as the short-range action of secreted guidance molecules (such as Slits and Semaphorins) could be mimicked in vitro by this assay 17,18 . Also stripe assay experiments were conducted to unravel potential guidance properties of extracellular matrix components 19,20 and of cell adhesion molecules of the IgG superfamily 21 .Of note, the stripe assay was employed as an in vitro assay to investigate the navigation responses of both axonal growth cones toward guidance cues and of migrating cells 4,22,23 . With respect to the latter, neural crest cells 22 and oligodendrocytes 23,24 , but also non-neuronal cells such as tumor cells, have been studied 25 .The assay allows assessment of guidance activity of established molecules and also testing potential guidance properties of hitherto uncharacterized molecules such as RGM, the Wnt signaling inhibitor SFRP1 or the morphogen Sonic h...

show abstract

“…Pioneering studies from Drescher et al (1995) identified a graded expression of ephrins (originally called repulsive axonal guidance signal or RAGS) in the optic tectum, and further work from this and other groups brought insight into their mechanism of action and intracellular cascades (see, for example, Nakamoto et al, 1996;Monschau et al, 1997;Yates et al, 2001;Hansen et al, 2004;Knoll and Drescher, 2004;Rashid et al, 2005). It is now generally accepted that in the retina and optic tectum, ephrins and Eph receptors can act as repulsive guidance cues distributed in opposing gradients.…”

Section: Ephrins Direct Thalamic Axons To Find Their Cortical Targetmentioning

confidence: 99%

Connecting thalamus and cortex: The role of ephrins

et al. 2006

View full text Add to dashboard Cite

The complex task of wiring up the brain during embryonic development is achieved by a multitude of guidance signals acting in complex combinations to drive growing axons to their proper targets. The somatosensory system provides an extensively studied model system featuring many universal mechanisms of neural development. In rodents, it constitutes an important model to study how precise topographic connections are achieved. Recent evidence suggests that the Eph/ephrin family of guidance molecules is of pivotal importance for the development of the somatosensory system. Members of Eph/ephrin family are thought to be involved in the global presorting of thalamic axons projecting to the cortex, in labeling specific cortical areas for innervation, in providing topographic cues within the target area, and in distinguishing cortical layers for intracortical wiring. The Eph/ephrin system also seems to contribute to the formation of specific corticothalamic feedback projections. So far, the functions of only a few members of the Eph/ephrin family have been examined, but expression analysis indicates complex combinatorial effects of these signaling molecules. Understanding the Eph/ephrin wiring code is expected to yield new insights into the development and plasticity of brain circuits involved in higher functions.

show abstract

Topographic-Specific Axon Branching Controlled by Ephrin-As Is the Critical Event in Retinotectal Map Development

Cited by 191 publications

References 48 publications

Ephrin-A5 restricts topographically specific arborization in the chick retinotectal projection in vivo

Ephrin-A5 restricts topographically specific arborization in the chick retinotectal projection in vivo

Stripe assay to examine axonal guidance and cell migration

Connecting thalamus and cortex: The role of ephrins

Contact Info

Product

Resources

About