Endocytosis of EphA receptors is essential for the proper development of the retinocollicular topographic map

Yoo, Sooyeon; Kim, Yujin; Noh, Hyun; Lee, Haeryung; Park, Eunjeong; Park, Soochul

doi:10.1038/emboj.2011.44

Cited by 32 publications

(37 citation statements)

References 44 publications

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“…37,38 To examine the expression patterns of ephrin-A5 or EphA7 along the DM, we generated bacterial artificial chromosome (BAC) transgenic lines in which the ephrin-A5 or EphA7 promoter drives expression of the LacZ reporter, as described (Supplementary Figure 1G). 39,40 Consistent with previous studies, X-gal (X-gal, 5-bromo-4-chloro-3-indolyl-b-D-galactopyranoside) staining of eA5-LacZ BAC embryos at E11.5 revealed that LacZ expression recapitulated the expression pattern of ephrin-A5 in brain regions such as the posterior midbrain, the DM of the diencephalon, and the medial region of the posterior telencephalon (Figures 2a and b). Similarly, reporter expression of the EphA7-LacZ BAC embryo is consistent with a previous report showing that EphA7 is expressed in the DM of the diencephalon and the lateral region of the posterior telencephalon (Figures 2i and j).…”

Section: Resultssupporting

confidence: 90%

“…ephrin-A5. 39 For this purpose, a targeting vector consisting of floxed green fluorescent protein (GFP) and ephrin-A5-Fc was inserted into the first exon of ephrin-A5 BAC in which only GFP expression occurs because of stop signals between GFP and ephrin-A5-Fc (Figure 3a). Transgenic mice carrying a recombinant BAC, eA5-eA5Fc, were crossed with Wnt1-Cre to induce specific expression of ephrin-A5-Fc in the DM of the diencephalon and mesencephalon ( Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

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EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development

et al. 2012

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EphAs and ephrin-As have been implicated in the morphogenesis of the developing brain. We found that EphA7 and ephrin-A5 are coexpressed in the dorsal midline (DM) of the diencephalon and anterior mesencephalon. Interestingly, programmed cell death (PCD) of the neural epithelial cells normally found in this region was reduced in ephrin-A5/ephrin-A2 dual-deficient embryos. In contrast, in vivo expression of ephrin-A5-Fc or full-length ephrin-A5 strongly induced apoptosis in neural epithelial cells and was accompanied by severe brain malformation during embryonic development. Expression of ephrinA5-Fc correlated with apoptosis of EphA7-expressing cells, whereas null mutation of ephrin-A5 resulted in the converse phenotype. Importantly, null mutation of caspase-3 or endogenous ephrin-A5 attenuated the PCD induced by ectopically overexpressed ephrin-A5. Together, our results suggest that brain region-specific PCD may occur in a region where EphAs cluster with neighboring ephrin-As through cell-cell contact.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development

et al. 2012

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“…We thus used ephrin A5 (Efna5) BAC transgenic lines that contain sufficient cis-acting elements to drive expression of GFP in the pattern of endogenous Efna5 expression (Yoo et al, 2011). In horizontal sections along the naso-temporal axis, we observed that Efna5 expression begins in the optic vesicle at E9.5.…”

Section: Resultsmentioning

confidence: 99%

“…Ephrin A5 BAC transgenic mice expressing GFP have been previously described (Yoo et al, 2011). To generate the EphB2-GFP BAC targeting vector, we amplified homologous arms A (1008 bp) and B (909 bp) flanking the mouse Ephb2 translation start site (ATG) using PCR with the following primers: 5′-GGCCAAGTCGGCCGAGTA-GGGGCTGTCGCTA-3′ (forward primer for A arm); 5′-GAGCTCTGC-TGCGCTGCCCGGAGCCT-3′ (reverse primer for A arm); 5′-ATGCATCATCTTGCCGAGGCTTTGTA-3′ (forward primer for B arm); and 5′-ATGCATAATTCGACCCATCTGGCTTC-3′ (reverse primer for B arm).…”

Section: Bac Modification Transgenic and Knockout Micementioning

confidence: 99%

Proper closure of the optic fissure requires ephrin A5-EphB2-JNK signaling

et al. 2016

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The development of complex organs such as the eye requires a delicate and coordinated balance of cell division and cell death. Although apoptosis is prevalent in the proximoventral optic cup, the precise role it plays in eye development needs to be investigated further. In this study, we show that reduced apoptosis in the proximoventral optic cup prevents closure of the optic fissure. We also show that expression of ephrin A5 (Efna5) partially overlaps with Eph receptor B2 (Ephb2) expression in the proximoventral optic cup and that binding of EphB2 to ephrin A5 induces a sustained activation of JNK. This prolonged JNK signal promotes apoptosis and prevents cell proliferation. Thus, we propose that the unique cross-subclass interaction of EphB2 with ephrin A5 has evolved to function upstream of JNK signaling for the purpose of maintaining an adequate pool of progenitor cells to ensure proper closure of the optic fissure.

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“…Eph-ephrin signalling often initiates contact repulsion, causing de-adhesion, collapse of cell processes, and cell detachment. However, the initial binding between Eph and ephrins is high affinity, forming a stable linkage between the interacting proteins [47,369]. To counter this attachment, ephrins bind a protease that becomes activated by Eph-ephrin signalling [119].…”

Section: Overview: Ephs Ephrins and Topographic Mapsmentioning

confidence: 99%

In vivo imaging of the zebrafish retinotectal map

Kita¹

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The precise neural connections that form during development support the creation of a functioning nervous system. An accessible experimental model for this process is the retinotectal system in zebrafish, which develops rapidly and can be observed in vivo throughout its establishment using confocal time-lapse imaging. The retinotectal connection is topographic, such that the spatial relationships of the retinal ganglion cell (RGC) somas in the retina are maintained by the arborization locations of their axons on the tectum. However, how axons find their correct arborization location on this topographic map is still debated. While initial studies suggested that zebrafish RGCs were guided directly by a growth cone to their target on the map, recent observations challenge that claim. My work characterizes a novel guidance pattern for RGCs pathfinding on the tectum. Once pathfinding through the tectal neuropil, zebrafish RGCs continually add and remove branches. The directionality of the branches is biased, in that more are pointing towards the eventual arborization zone than away from it. Growth cones, which tip some of the branches, extend mostly in straight lines rather than progressing through turns towards the target. The distance to the target is decreased by the axon branching in many directions, and selecting a branch that decreases the distance to support further rounds of branching. The mechanism of biased branching could be based on known types of input that guide connectivity during development and we focused on the contributions of activity and molecular guidance cue gradients.We hypothesized that silencing neural activity using TTX could alter the navigation methods used, but many of the characteristics of axon pathfinding were similar despite global silencing. The area covered by the branches during pathfinding decreases when the retinotectal system is electrically silent, but the biased branch ratio remains. Several measures of the arbors after the target is reached show differing patterns without activity, supporting previous evidence that activity is an important regulation of arborization dynamics.Molecularly, the retinotectal map is established through gradients of guidance cues that guide axons to their target location, cause them to stop advancing, and elaborate a terminal arbor. Through morpholino knock down we observe the different effects that two of these guidance proteins, ephrin-A5b and ephrin-A2, have on individual axons as they navigate.iii Overall, knockdown of ephrin-A5b tends to increase length, area and number of branches, while the knockdown of ephrin-A2 has the opposite effect on these measures. Additionally, a subset of axons show phenotypes that are masked by the grouped data, where several form loops instead of travelling in rather straight trajectories, or alternatively, grow long and remain relatively branchless as they travel towards the caudal extent of the tectum.The following thesis gives quantitative, detailed insight into some of the ways that activity and molec...

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Endocytosis of EphA receptors is essential for the proper development of the retinocollicular topographic map

Cited by 32 publications

References 44 publications

EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development

EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development

Proper closure of the optic fissure requires ephrin A5-EphB2-JNK signaling

In vivo imaging of the zebrafish retinotectal map

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