Loss-of-Function Analysis of EphA Receptors in Retinotectal Mapping

Feldheim, David A.; Nakamoto, Masaru; Osterfield, Miriam; Gale, Nicholas W.; DeChiara, Thomas M.; Rohatgi, Rajat; Yancopouloš, George D.; Flanagan, John G.

doi:10.1523/jneurosci.0239-03.2004

Cited by 141 publications

(128 citation statements)

References 56 publications

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“…Indeed, in the absence of ephrin-A5 anteroposterior gradient in the superior colliculus (SC) or EphA naso-temporal gradient in the retina, temporal axons (TAs) shift posteriorly. Nasal axons (NAs) therefore face increased competition in posterior SC, lose their affinity for this region and spread out anteriorly 14,45 . On the basis of gain-and loss-of-function analysis, a repulsion/competition model accounting for normal mapping has been proposed 14,46 .…”

Section: Discussionmentioning

confidence: 99%

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

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Section: Discussionmentioning

confidence: 99%

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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“…Mapping along the N-T axis of these connections has been proposed to use a combination of EphA/ephrin-A signaling (Feldheim et al, 1998(Feldheim et al, , 2000(Feldheim et al, , 2004Frisén et al, 1998;Rashid et al, 2005), patterned retinal activity-dependent axonal refinement (Ruthazer and Cline, 2004;Torborg and Feller, 2005), and axonaxon competition to ensure innervation of the entire target (Walsh et al, 1983;Garraghty, 1995); however, the relative roles of each are not known. Here, using anterograde labeling of RGCs from four retinal poles, we provided the first thorough characterization of the topographic retinogeniculate projection in wildtype mice.…”

Section: Discussionmentioning

confidence: 99%

“…1, available at www.jneurosci.org as supplemental material). Mice mutant for ephrins-A2 and -A5 (Frisén et al, 1998;Feldheim et al, 2000), EphA5 (Feldheim et al, 2004), and EphA7 (Rashid et al, 2005) all have topographic mapping defects along the anterior-posterior (A-P) axis of the SC; however, in none of these mutants is topography completely abolished.…”

Section: Introductionmentioning

confidence: 99%

Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

Pfeiffenberger

Yamada²,

Feldheim³

2006

J. Neurosci.

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The development of topographic maps in the primary visual system is thought to rely on a combination of EphA/ephrin-A interactions and patterned neural activity. Here, we characterize the retinogeniculate and retinocollicular maps of mice mutant for ephrins-A2, -A3, and -A5 (the three ephrin-As expressed in the mouse visual system), mice mutant for the ␤2 subunit of the nicotinic acetylcholine receptor (that lack early patterned retinal activity), and mice mutant for both ephrin-As and ␤2. We also provide the first comprehensive anatomical description of the topographic connections between the retina and the dorsal lateral geniculate nucleus. We find that, although ephrin-A2/A3/A5 triple knock-out mice have severe mapping defects in both projections, they do not completely lack topography. Mice lacking ␤2-dependent retinal activity have nearly normal topography but fail to refine axonal arbors. Mice mutant for both ephrin-As and ␤2 have synergistic mapping defects that result in a near absence of map in the retinocollicular projection; however, the retinogeniculate projection is not as severely disrupted as the retinocollicular projection is in these mutants. These results show that ephrin-As and patterned retinal activity act together to establish topographic maps, and demonstrate that midbrain and forebrain connections have a differential requirement for ephrin-As and patterned retinal activity in topographic map development.

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“…1e). We also performed in situ hybridization to detect ephrin-A5 mRNA [28][29][30]41 . This confirmed the presence of an outer > inner gradient of ephrin-A5 mRNA in the LGN that could be seen in both the horizontal (Fig.…”

Section: Epha and Ephrin-a Expression In Postnatal Visual Systemmentioning

confidence: 99%

“…These observations indicate that the nasal-retina versus temporal-retina distinction (as opposed to the left-eye versus righteye distinction) is the key parameter for patterning of eye-specific projections in the LGN. Numerous experiments carried out in lower vertebrates and mice indicate that ephrin-As mediate retinotopic mapping of the nasal-temporal axis in the SC and LGN [24][25][26][27][28][29][30] . We wanted to test whether ephrin-As have a second function in retino-geniculate mapping: dictating the stereotyped patterning of the eye-specific LGN layers.…”

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confidence: 99%

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

et al. 2005

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Axon guidance cues contributing to the development of eye-specific visual projections to the lateral geniculate nucleus (LGN) have not previously been identified. Here we show that gradients of ephrinAs and their receptors (EphAs) direct retinal ganglion cell (RGC) axons from the two eyes into their stereotyped pattern of layers in the LGN. Overexpression of EphAs in ferret RGCs using in vivo electroporation induced axons from both eyes to misproject within the LGN. The effects of EphA overexpression were competition-dependent and restricted to the early postnatal period. These findings represent the first demonstration of eye-specific pathfinding mediated by axon guidance cues and, taken with other reports, indicate that ephrin-As can mediate several mapping functions within individual target structures.In mammals, retinal ganglion cell (RGC) axons are segregated into eye-specific layers in the lateral geniculate nucleus (LGN). Early in development, however, retinogeniculate axons from the two eyes are intermingled 1-3 . The segregation of eye-specific projections into layers is an established model system for studying axon targeting during development 4 . Technically, the term "layers" refers to discrete cellular groupings. However, "eye-specific LGN layers" is also used to refer to the regions of stereotyped size, shape and position formed by RGC axons arising from each eye. (Hereafter we use the term "layers" only in this latter sense.) The regularity of eye-specific layers is a distinguishing feature of mammalian brains; their spatial arrangement is different between, but invariant within, species 5 . In carnivores such as cats and ferrets, layer A contains axons from the contralateral eye and always resides in the inner portion of the LGN, whereas layer A1 contains axons from the ipsilateral eye and always resides in the outer LGN 5 . This invariance is in bold contrast to eye-specific projections found elsewhere along the visual pathway, such as eye-specific patches in the superior colliculus (SC) 6 or ocular dominance columns in visual cortex 7 , which vary tremendously across individuals of a given species in terms of their size, shape and position.Correspondence should be addressed to B.C. (bxchapman@ucdavis.edu). 4 Present address: Department of Neurobiology, Fairchild Building, Stanford University School of Medicine, Palo Alto, California 94305, USA.Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptNumerous studies have shown that altering neural activity perturbs eye-specific retinogeniculate segregation 8-12 . However, the invariant positioning of eye-specific LGN layers cannot be explained by purely activity-dependent mechanisms 13,14 and recent data have challenged the idea that neural activity plays a direct, instructive role in segregation of eyespecific projections to ...

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Loss-of-Function Analysis of EphA Receptors in Retinotectal Mapping

Cited by 141 publications

References 56 publications

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

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