Eph/Ephrin signalling maintains eye field segregation from adjacent neural plate territories during forebrain morphogenesis

Abstract

During forebrain morphogenesis, there is extensive reorganisation of the cells destined to form the eyes, telencephalon and diencephalon. Little is known about the molecular mechanisms that regulate region-specific behaviours and that maintain the coherence of cell populations undergoing specific morphogenetic processes. In this study, we show that the activity of the Eph/Ephrin signalling pathway maintains segregation between the prospective eyes and adjacent regions of the anterior neural plate during the early stages of forebrain morphogenesis in zebrafish. Several Ephrins and Ephs are expressed in complementary domains in the prospective forebrain and combinatorial abrogation of their activity results in incomplete segregation of the eyes and telencephalon and in defective evagination of the optic vesicles. Conversely, expression of exogenous Ephs or Ephrins in regions of the prospective forebrain where they are not usually expressed changes the adhesion properties of the cells, resulting in segregation to the wrong domain without changing their regional fate. The failure of eye morphogenesis in rx3 mutants is accompanied by a loss of complementary expression of Ephs and Ephrins, suggesting that this pathway is activated downstream of the regional fate specification machinery to establish boundaries between domains undergoing different programmes of morphogenesis.

Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion

“…Ephrin/ Eph signaling mediates cell dispersal required for retinal progenitors to access the Xenopus eye field (Moore et al, 2004), and allows the zebrafish eye field to remain segregated from adjacent neural plate regions (Cavodeassi et al, 2013). Subsequent morphogenesis of the eye field may involve non-canonical Wnt signaling (Cavodeassi et al, 2005).…”

“…For example, transmembrane ephrins and their Eph receptors mediate repellent interactions that prevent mixing between the cells of adjacent hindbrain rhombomeres (Cooke et al, 2005;Kemp et al, 2009). Ephrin/Eph signaling also segregates somitic cells (Watanabe and Takahashi, 2010), ectodermal and mesodermal tissue (Rohani et al, 2011), and anterior neural plate domains (Cavodeassi et al, 2013). Other than these few examples, however, we know little of the molecular mechanisms that mediate tissue cohesion during development.…”

Ephrin-Eph signaling in embryonic tissue separation

“…We present in Figure 3 simplified maps relevant for the 6 boundaries that have been functionally studied: dorsal and ventral ectoderm-mesoderm boundaries, 35,38 notochord-presomitic mesoderm, 36 hindbrain, 33,39,40 somites, 32,41,42 and eye field. 37 We have selected in each case the pattern from the species where most functional studies were performed. Available data for the hindbrain and somitic mesoderm indicate that these patterns are largely conserved across vertebrates, with some variations though.…”

“…36 Eye field Ephrin/Eph depletion in zebrafish also led to eye defects, apparently due to failure of cells of the prospective optic vesicle to sort from the surrounding brain field. 37 The process seems to rely on redundant signals (Fig. 3F), since double ephrinB1 and B2a depletion produced relatively mild phenotypes, which were made more severe by simultaneous depletion of EphA4a.…”

“…35,36 At later stages, they are also involved in the individualization of the eye field within the anterior neuroderm. 37 It appears that these repulsive cues control virtually all tissue separation events so far investigated in vertebrate embryos, and it is tempting to speculate that these finding reflect a general mechanism of tissue separation based on "negative affinities" that trigger contact inhibition at heterotypic contacts.…”