On the turning of Xenopus retinal axons induced by ephrin-A5 (original) (raw)
Related papers
Neuron, 2002
al., 2000). In chick retina, the expression of both EphB receptors and ephrin-B ligands is under the control of Ephrin-B and EphB are distributed in matching dorsothe transcription factors cVax and Tbx5, respectively, ventral gradients in the embryonic Xenopus visual syswhich play a role in the early D-V patterning of the retina tem with retinal axons bearing high levels of ligand (Schulte et al., 1999; Koshiba-Takeuchi et al., 2000). (dorsal) projecting to tectal regions with high receptor Misexpression of both cVax2 and Tbx5 in chick retina expression (ventral). In vitro stripe assays show that causes topographic targeting errors of RGC axons along dorsal retinal axons prefer to grow on EphB receptor the D-V axis of the tectum (Schulte et al., 1999; Koshibastripes supporting an attractive guidance mechanism. Takeuchi et al., 2000), further suggesting a possible role In vivo disruption of EphB/ephrin-B function by appliof B-type Eph family molecules in D-V mapping. cation of exogenous EphB or expression of dominantnegative ephrin-B ligand in dorsal retinal axons causes Unlike the A-P axis, in the D-V axis, RGC axons exthese axons to shift dorsally in the tectum, while mispressing the highest level of EphB receptors project to expression of wild-type ephrin-B in ventral axons the area of the tectum with the highest ligand exprescauses them to shift ventrally. These dorsoventral tarsion. For example, in chick embryos, EphB2 is exgeting errors are consistent with the hypothesis that pressed on RGC axons from the ventral half of the retina an attractive mechanism that requires ephrin-B cyto-(Holash and Pasquale, 1995); and a ligand for this recepplasmic domain is critical for retinotectal mapping in tor, ephrin-B1, is maximally expressed in the dorsal tecthis axis. tum (Braisted et al., 1997). This suggests that ephrin-Bs might be implicated in attractive rather than repulsive Introduction guidance (Braisted et al., 1997; O'Leary and Wilkinson, 1999). However, other results show that ephrin-Bs can The development of appropriate connections between act as repulsive guidance cues for EphB receptorneurons and target cells in the brain is of fundamental expressing neurons (Meima et al., 1997; Wang and Animportance in the visual system, where retinal ganglion derson, 1997; Kullander et al., 2001a; Yokoyama et al., cell (RGC) axons project a topographic representation 2001)
Cell, 1995
The results of previous in vitro experiments indicate that a glycosylphosphatidylinositol (GPI)-anchored protein may play an important role in the guidance of temporal retinal axons during the formation of the topographically ordered retinotectal projection. We have purified and cloned a GPI-anchored, 25 kDa glycoprotein that is a good candidate for a molecule involved in this process. During the time of innervation by retinal ganglion cells, this protein is gradedly expressed in the posterior part of the developing tectum. In two different in vitro assay systems, the recombinant protein induces growth cone collapse and repulsion of retinal ganglion cell axons. These phenomena are observed for axons of temporal as well as nasal origin, indicating that an additional activity may be necessary to confer the nasotemporal specificity observed in previous assays. We named the protein RAGS (for repulsive axon guidance signal). The sequence of RAGS shows significant homology to recently identified ligands for receptor tyrosine kinases of the Eph subfamily.
Ephrin-B Regulates the Ipsilateral Routing of Retinal Axons at the Optic Chiasm
Neuron, 2000
In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when these metamorphic RGCs are grafted into embryos, they project contralaterally, suggesting that the embryonic chiasm lacks signals that guide axons ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm, ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs. Ephrin-B is also found in the chiasm of mammals, which have ipsilateral projections, but not in the chiasm of fish and birds, which do not. These results suggest that ephrin-B/EphB interactions play a key role in the sorting of axons at the vertebrate chiasm.
Ephrin-B2 and EphB1 Mediate Retinal Axon Divergence at the Optic Chiasm
Neuron, 2003
In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when these metamorphic RGCs are grafted into embryos, they project contralaterally, suggesting that the embryonic chiasm lacks signals that guide axons ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm, ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs. Ephrin-B is also found in the chiasm of mammals, which have ipsilateral projections, but not in the chiasm of fish and birds, which do not. These results suggest that ephrin-B/EphB interactions play a key role in the sorting of axons at the vertebrate chiasm.
Development (Cambridge, England), 1997
The isolation and characterisation of two zebrafish Eph receptor ligand cDNAs which we have called zfEphL3 and zfEphL4 is described. These genes are expressed in the presumptive midbrain of developing embryos from 6 somites. By 24 hours L3 is expressed throughout the midbrain including the region of the presumptive tectum whereas L4 is strongly expressed in the midbrain caudal to the presumptive tectum. At later stages of development L3 is expressed in a graded fashion throughout the tectum and L4 is maintained at its posterior margin. Growth cone collapse and pathway selection assays demonstrate that both these proteins have a collapse activity for retinal ganglion cells. When faced with a choice of substrate on which to grow, temporal axons from chick retinal ganglion cells selectively avoided membranes from Cos cells transfected with L3, whereas nasal axons did not. Both temporal and nasal axons avoided membranes from Cos cells transfected with L4. The expression patterns togethe...
Molecular Biology of Axon Guidance
Neuron, 1996
of a very exciting and intensive meeting that took place on September 12-14, 1996, at the EMBL in Heidelberg. Instituto Cajal, CSIC 28002 Madrid The workshop, entitled "Molecular Biology of Axon Guidance," gathered a forum of 26 speakers and some Spain 90 people in total, who enthusiastically presented and discussed the recent advances in the field. I will summarize the meeting in this review, emphasizing some of the More than a century ago, Cajal published one of his new data presented. most significant contributions, the discovery of the The topics of the meeting were quite varied but many growth cone as the terminal structure of the developing of the speakers concentrated on axonal guidance in the neuronal cell. This finding was a crucial step in the estabtwo models used to describe the growth cone and the lishment of the theory that neurons develop as individual chemoaffinity theory, namely the midline and the retinocells. tectal system; the starring molecules were members of ".. This fibre [of the commissural neuron] ends...in an the collapsin/semaphorin family, the netrins, and the enlargement which may be rounded and subtle, but that Eph-related receptor family and their ligands. may also adopt a conical appearance. This latter we shall name the growth cone, that at times displays fine The Eph-Related Receptor Family and short extensions...which appear to insinuate themand Their Ligands selves between the surrounding elements, relentlessly Receptor tyrosine kinases (RTKs) have been subdivided forging a path through the interstitial matrix" (Ramó n y into 14 different families according to sequence similar-Cajal, 1890a, Figure 1). ity, mainly based on their extracellular domains. Over the past five years, the Eph family of receptors (named Apart from a very precise definition of the growth cone, one can also find in Cajal's writings the origin of for the first member of the family; Hirai et al., 1987) has attracted a lot of attention from people working on axon the neurotropic theory and of the mechanism of axonal pathfinding. Two years later, after the analysis of the pathfinding. Although this family had been thought to be excellent candidates to play important roles in the developing retinotectal connections, and by extrapolation from Pfeffer's chemotaxis theory, Cajal proposed development of the vertebrate embryo, until recently they were were referred to as "orphan receptors" be-that developing neurons possessed chemotactic properties that would guide axons to their targets. He sug-cause of the absence of known ligands that could bind to them. Today, the Eph family is the largest subfamily gested that the growth cone would be guided by "chemical flows" that they would follow to find the secretory of RTKs, comprising at least 14 members. These bind to a novel family of ligands with eight members already target (Ramó n y Cajal, 1893). This suggestion was neglected for many years in favor of the mechanical theory, described and are considered essential players in many different processes during embryonic development, in-but was brought to light again in the 1940s. Sperry carried out a long series of experimental manipulations cluding the development of the vertebrate nervous system. in the newt that led him to suggest the existence of complementary and recognizable cytochemical tags What are the characteristics of the Eph receptor family? The extracellular region of the receptors contains present in the retina and its target, the optic tectum. Twenty years later, he formulated the chemoaffinity the-an immunoglobulin-like domain, a Cys-rich domain and two fibronectin type III domains, and the cytoplasmic ory in which he postulated the existence of at least two cytochemical gradients superimposed both in the retina region, a single kinase catalytic domain. Different members of the family have been cloned in many vertebrates and the tectum that would provide each axon with a particular target "latitude and longitude," allowing the species, and the sequence similarity among the orthologs is extremely high. The cloning of the first ligand formation of a precise topographic map (Sperry, 1963). We now know that Sperry was partly correct in saying for this receptor family was the result of a very difficult hunting task, looking for receptor binding activity in con-that topographic maps are generated by the existence of chemoaffinity labels, but also that the ultimate refine-ditioned media obtained from more than a hundred cell lines (Bartley et al., 1994). From then on, and at an im-ment of these maps depends on neuronal activity and trophic support. In any case, the growth cones encoun-pressive rate, the identification of seven more ligands has been reported to date. One very important character a great variety of guiding signals, either attractive or repellent that, in addition, can be diffusible or attached teristic of these ligands is that they are all membraneattached proteins, either by a glycophosphotidylinositol to the cell membrane or to the extracellular matrix. We have had to wait until recently to learn the identity of (GPI) linkage or through a transmembrane (TM) domain. Therefore, whenever we talk about any Eph receptor-the actual molecules that do the job. The amount of information accumulated in the last few years through ligand interactions, we are talking about contact-dependent cell to cell communication, as the ligands require the cloning and functional analysis of some of these molecules precipitated the organization by Rudiger membrane attachment (or artificial clustering) for activity (Davis et al., 1994). This fact confers on them unique Klein (European Molecular Biology Laboratory [EMBL], Germany) and John Flanagan (Harvard Medical School) properties that suggest that the cellular responses to
Ephrin-A6, a New Ligand for EphA Receptors in the Developing Visual System
Developmental Biology, 2001
In the embryonic visual system, EphA receptors are expressed on both temporal and nasal retinal ganglion cell axons. Only the temporal axons, however, are sensitive to the low concentrations of ephrin-A ligands found in the anterior optic tectum. The poor responsiveness of nasal axons to ephrin-A ligands, which allows them to traverse the anterior tectum and reach their targets in the posterior tectum, has been attributed to constitutive activation of the EphA4 receptor expressed in these axons. EphA4 is highly expressed throughout the retina, but is preferentially phosphorylated on tyrosine (activated) in nasal retina. In a screen for EphA4 ligands expressed in chicken embryonic retina, we have identified a novel ephrin, ephrin-A6. Like ephrin-A5, ephrin-A6 has high affinity for EphA4 and activates this receptor in cultured retinal cells. In the embryonic day 8 (E8) chicken visual system, ephrin-A6 is predominantly expressed in the nasal retina and ephrin-A5 in the posterior tectum. Thus, ephrin-A6 has the properties of a ligand that activates the EphA4 receptor in nasal retinal cells. Ephrin-A6 binds with high affinity to several other EphA receptors as well and causes growth cone collapse in retinal explants, demonstrating that it can elicit biological responses in retinal neurons. Ephrin-A6 expression is high at E6 and E8, when retinal axons grow to their tectal targets, and gradually declines at later developmental stages. The asymmetric distribution of ephrin-A6 in retinal cells, and the time course of its expression, suggest that this new ephrin plays a role in the establishment of visual system topography.
Neuron Article p75NTR Mediates Ephrin-A Reverse Signaling Required for Axon Repulsion and Mapping
2015
Reverse signaling by ephrin-As upon binding EphAs controls axon guidance and mapping. Ephrin-As are GPI-anchored to the membrane, requiring that they complex with transmembrane proteins that trans-duce their signals. We show that the p75 neurotro-phin receptor (NTR) serves this role in retinal axons. p75NTR and ephrin-A colocalize within caveolae along retinal axons and form a complex required for Fyn phosphorylation upon binding EphAs, activating a signaling pathway leading to cytoskeletal changes. In vitro, retinal axon repulsion to EphAs by ephrin-A reverse signaling requires p75NTR, but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75NTR knockout mice have aberrant anterior shifts in retinal axon terminations in superior colliculus, consistent with diminished repellent activity mediated by graded ephrin-A reverse signaling induced by graded collic-ular EphAs. We conclude that p75NTR is a signaling partner for ephrin-As and the ephri...