Topographically Specific Effects of ELF-1 on Retinal Axon Guidance In Vitro and Retinal Axon Mapping In Vivo

Nakamoto, Masaru; Cheng, Hwai-Jong; Friedman, Glenn C.; McLaughlin, Todd; Hansen, Michael J.; Yoon, Cliff; O’Leary, Dennis D.M.; Flanagan, John G.

doi:10.1016/s0092-8674(00)80150-6

Cited by 413 publications

(339 citation statements)

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“…During development of the retinotectal map of the chick, which projects an image of the visual world from the retina to the tectum of the midbrain, two ligands, ephrin-A2 and ephrin-A5, are expressed in an anteroposterior gradient in the target Drescher et al, 1995), while their receptor EphA3 is expressed in the projecting retinal neurons, in a gradient along the matching nasotemporal axis . Assays of retinal axon responses have shown appropriate guidance e ects: ephrin-A5 can repel retinal axons in vitro (Drescher et al, 1995) with a topographically appropriate preference for temporal axons (Monschau et al, 1997), while ephrin-A2 can repel retinal axons in vitro and in vivo, also with a topographically appropriate specificity (Nakamoto et al, 1996). Ephrin-A2, ephrin-A5 and their receptor EphA3 thus have properties consistent with complementary positional axonal mapping labels of the type originally proposed by Sperry (1963).…”

Section: Introductionsupporting

confidence: 59%

“…In principle, the roof plate expression of ephrin-B3 could similarly act to inhibit axons from crossing to the contralateral side of the neural tube. The idea of a repellent activity for ephrin-B3 is particularly appealing in view of the axon repellent e ects shown for several other Eph family ligands: ephrin-A2, ephrin-A5, ephrin-B1 and ephrin-B2 (Drescher et al, 1995;Nakamoto et al, 1996;Wang and Anderson, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

et al. 1998

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The ephrins are a family of ligands that bind to Eph family receptor tyrosine kinases, and have been implicated in axon guidance and other patterning processes during vertebrate development. We describe here the identi®cation and characterization of murine ephrin-B3. The cDNA encodes a 340 amino acid transmembrane molecule, most closely related to the two other known transmembrane ligands, ephrin-B1 and ephrin-B2. In addition to homology in their extracellular receptor binding domains, these transmembrane ligands share striking homology between their cytoplasmic domains, with 31 of the last 34 amino acids of ephrin-B3 being identical to ephrin-B2, suggesting functional interactions of the cytoplasmic tail. While most Eph family ligands are promiscuous in their interactions with Eph receptors, binding studies with the ®ve receptors known to bind other transmembrane ligands only revealed a high a nity interaction of ephrin-B3 with EphB3, with a dissociation constant of approximately 1 nM. In situ hybridization of mouse embryos showed ephrin-B3 is expressed prominently at the dorsal and ventral midline of the neural tube, particularly in the¯oor plate, a structure with key functions in patterning the nervous system. The isolation of this ligand may help to elucidate the molecular basis of patterning activities at the neural tube midline.

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Section: Introductionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

et al. 1998

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“…The roles for Eph receptors and their ligands in cell-cell repulsion have been well established (Drescher et al, 1995;Nakamoto et al, 1996;Monschau et al, 1997;Frisen et al, 1998). To investigate whether the EphA8 signaling a ects cell adhesion, the same cell lines used for demonstrating Fyn association in vivo were tested for their properties to attach to culture dishes.…”

Section: Activation Of the Epha8 Receptor Attenuates Cell Attachmentmentioning

confidence: 99%

“…Repulsive modes of interaction between Eph receptors and their ligands have been proposed to set up topographic projections in the retinotectal or retinocollicular systems (Cheng et al, 1995;Drescher et al, 1995;Nakamoto et al, 1996;Monschau et al, 1997;Frisen et al, 1998), the hippocampal and thalamic neurons (Gao et al, 1996(Gao et al, , 1998, and the guidance of migrating neural crest cells and motor axons to the rostral halves of developing somites (Krull et al, 1997;Wang and Anderson, 1997). Abnormalities in the formation of brain commissures have been observed in mice lacking EphB2, EphB3 and EphA8 receptors Orioli et al, 1996;Park et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

Choi

Park

1999

Oncogene

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Eph-related receptors and their ephrin ligands are highly conserved protein families which play important roles in targeting axons and migrating cells. In this study we have examined the functional roles of two major autophosphorylation sites, Tyr-615 and Tyr-838, in the EphA8 receptor. Two-dimensional phosphopeptide mapping analysis demonstrated that Tyr-615 and Tyr-838 constitute major autophosphorylation sites in EphA8. Tyr-615 was phosphorylated to the highest stoichiometry, suggesting that phosphorylation at this site may have a physiologically important role. Upon conservative mutation of Tyr-838 located in the tyrosine kinase domain, the catalytic activity of EphA8 was strikingly reduced both in vitro and in vivo, whereas a mutation at Tyr-615 in the juxtamembrane domain did not impair the tyrosine kinase activity. In vitro binding experiments revealed that phosphorylation at Tyr-615 in EphA8 mediates the preferential binding to Fyn-SH2 domain rather than Src and Ras GTPase-activating protein (Ras GAP)-SH2 domains. Additionally, a high level of EphA8 was detected in Fyn immunoprecipitates in intact cells, indicating that EphA8 and Fyn can physically associate in vivo. In contrast, the association of full-length Fyn to EphA8 containing mutation at either Tyr-615 or Tyr-838 was greatly reduced. These data indicate that phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for e cient phosphorylation at Tyr-615 as well as other major sites. Finally, it was observed that cell attachment responses are attenuated by overexpression of wild type EphA8 receptor but to much less extent by EphA8 mutants lacking phosphorylation at either Tyr-615 or Tyr-838. Furthermore, transient expression of kinase-inactive Fyn in EphA8-overexpressing cells blocked cell attachment responses attenuated by the EphA8 signaling. We therefore propose that Fyn kinase is one of the major downstream targets for the EphA8 signaling pathway leading to a modi®cation of cell adhesion, and that autophosphorylation at Tyr-838 is critical for positively regulating the EphA8 signaling event.

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“…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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Topographically Specific Effects of ELF-1 on Retinal Axon Guidance In Vitro and Retinal Axon Mapping In Vivo

Cited by 413 publications

References 34 publications

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

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

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