Opposing Gradients of Ephrin-As and EphA7 in the Superior Colliculus Are Essential for Topographic Mapping in the Mammalian Visual System

Rashid, T.; Upton, Amy L.; Blentic, Aida; Ciossek, Thomas; Knöll, Bernd; Thompson, Ian D.; Drescher, Uwe

doi:10.1016/j.neuron.2005.05.030

Cited by 157 publications

(206 citation statements)

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“…For the stripe assay using purified proteins rather than crude membrane fractions 1 (B), a modified protocol of the initially published work is employed 4,36 . In option B we describe a protocol preparing carpets of purified proteins belonging to the ephrin-A family of repulsive axon guidance molecules 34,35 .…”

Section: Procedures 1|mentioning

confidence: 99%

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Stripe assay to examine axonal guidance and cell migration

et al. 2007

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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...

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Section: Procedures 1|mentioning

confidence: 99%

“…4. Reduce receptor-ligand interaction of axons with carpet molecules by exogenously adding purified receptors or ligands into the medium 36,38 .…”

Section: Box 1 | Controls In Stripe Assay Experimentsmentioning

confidence: 99%

Stripe assay to examine axonal guidance and cell migration

et al. 2007

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“…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

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Connecting thalamus and cortex: The role of ephrins

et al. 2006

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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.

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“…Brown et al (2000) did not report anterior injections and so this prediction is yet to be tested. The EphA7 knock-out (Rashid et al, 2005) is modelled by complete removal of the reverse signalling pathway. This is a stronger manipulation than in the phenotype, where there is still a gradient of EphA4 in the SC.…”

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Retinocollicular mapping explained?

Sterratt

Hjorth

2013

Vis Neurosci

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We review and comment on Grimbert & Cang's (2012) model of the development of topographically ordered maps from the retina to the superior colliculus. This model posits a phase in which arbours are created in zones permitted by Eph and ephrin signalling, followed by a phase in which activity-dependent synaptic plasticity refines the map. We show that it is not possible to generate the arborization probability functions used in Grimbert & Cang's simulations using gradients of Ephs and ephrins and the interaction mechanism that Grimbert & Cang propose in their results. Furthermore, the arborization probabilities we do generate are far less sharp than we imagine truly "permissive" ones would be. It remains to be seen if maps can be generated from the non-permissive arborization probabilities generated from gradients.Keywords visual system; topography; computational modelling; chemoaffinity; retinal waves CommentaryThe extensive experimental and theoretical investigation of the development of topographically ordered maps from the retina to its targets ( Figure 1A) has led to two important theories of map development: molecular signalling and activity-dependent synaptic plasticity (Goodhill & Xu, 2005). In theories of molecular signalling, retinal ganglion cell (RGC) growth cones bear receptors in different densities depending on the location of the RGC soma in the retina, and these receptors are activated by ligands expressed in cells in the superior colliculus (SC) at levels depending on their location. This confers on each RGC a preferred location in the SC, which, depending on the pattern of receptor and ligand expression, is not necessarily its correct topographical position. Activitydependent synaptic plasticity of RGC-SC synapses along with correlated activity in the retina can also, in theory, lead to map formation, though extra cues are needed to ensure the orientation of the map is correct (Willshaw & von der Malsburg, 1976). In both theories other mechanisms, such as competition, may be required for a normal topographic map to form.There is experimental evidence that both molecular signalling and activity-dependent synaptic plasticity are involved in map formation. In support of molecular signalling, the Eph and ephrin families of molecules are expressed in gradients along the axes of the retina and colliculus, and their disruption genetically leads to disrupted maps (Feldheim & O'Leary, 2010;Cang & Feldheim, 2013). In support of activity-dependent synaptic plasticity, correlated activity exists in the retina in the form of retinal waves, and its disruption leads to impaired map precision (Torborg & Feller, 2005). Thus the two theories are complementary and the questions centre around the exact form and role of each mechanism and how they interact.Grimbert & Cang (2012) use a computational model to address the roles of activitydependent synaptic plasticity and molecular signalling in the development of topographically ordered maps from the retina to the SC. In contrast to previous models where mole...

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Opposing Gradients of Ephrin-As and EphA7 in the Superior Colliculus Are Essential for Topographic Mapping in the Mammalian Visual System

Cited by 157 publications

References 59 publications

Stripe assay to examine axonal guidance and cell migration

Stripe assay to examine axonal guidance and cell migration

Connecting thalamus and cortex: The role of ephrins

Retinocollicular mapping explained?

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