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A novel function for Hedgehog signalling in retinal pigment epithelium differentiation 总被引:7,自引:0,他引:7
Perron M Boy S Amato MA Viczian A Koebernick K Pieler T Harris WA 《Development (Cambridge, England)》2003,130(8):1565-1577
Sonic hedgehog is involved in eye field separation along the proximodistal axis. We show that Hh signalling continues to be important in defining aspects of the proximodistal axis as the optic vesicle and optic cup mature. We show that two other Hedgehog proteins, Banded hedgehog and Cephalic hedgehog, related to the mouse Indian hedgehog and Desert hedgehog, respectively, are strongly expressed in the central retinal pigment epithelium but excluded from the peripheral pigment epithelium surrounding the ciliary marginal zone. By contrast, downstream components of the Hedgehog signalling pathway, Gli2, Gli3 and X-Smoothened, are expressed in this narrow peripheral epithelium. We show that this zone contains cells that are in the proliferative state. This equivalent region in the adult mammalian eye, the pigmented ciliary epithelium, has been identified as a zone in which retinal stem cells reside. These data, combined with double labelling and the use of other retinal pigment epithelium markers, show that the retinal pigment epithelium of tadpole embryos has a molecularly distinct peripheral to central axis. In addition, Gli2, Gli3 and X-Smoothened are also expressed in the neural retina, in the most peripheral region of the ciliary marginal zone, where retinal stem cells are found in Xenopus, suggesting that they are good markers for retinal stem cells. To test the role of the Hedgehog pathway at different stages of retinogenesis, we activated the pathway by injecting a dominant-negative form of PKA or blocking it by treating embryos with cyclopamine. Embryos injected or treated at early stages display clear proximodistal defects in the retina. Interestingly, the main phenotype of embryos treated with cyclopamine at late stages is a severe defect in RPE differentiation. This study thus provides new insights into the role of Hedgehog signalling in the formation of the proximodistal axis of the eye and the differentiation of retinal pigment epithelium. 相似文献
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Wnt2b/beta-catenin-mediated canonical Wnt signaling determines the peripheral fates of the chick eye
Wnt signaling orchestrates multiple aspects of central nervous system development, including cell proliferation and cell fate choices. In this study, we used gene transfer to activate or inhibit canonical Wnt signaling in vivo in the developing eye. We found that the expression of Wnt2b or constitutively active (CA) beta-catenin inhibited retinal progenitor gene (RPG) expression and the differentiation of retinal neurons. In addition, Wnt signal activation in the central retina was sufficient to induce the expression of markers of the ciliary body and iris, two tissues derived from the peripheral optic cup (OC). The expression of a dominant-negative (DN) allele of Lef1, or of a Lef1-engrailed fusion protein, led to the inhibition of expression of peripheral genes and iris hypoplasia, suggesting that canonical Wnt signaling is required for peripheral eye development. We propose that canonical Wnt signaling in the developing optic vesicle (OV) and OC plays a crucial role in determining the identity of the ciliary body and iris. Because wingless (wg) plays a similar role in the induction of peripheral eye tissues of Drosophila, these findings indicate a possible conservation of the process that patterns the photoreceptive and support structures of the eye. 相似文献
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Kwan KM Otsuna H Kidokoro H Carney KR Saijoh Y Chien CB 《Development (Cambridge, England)》2012,139(2):359-372
Optic cup morphogenesis (OCM) generates the basic structure of the vertebrate eye. Although it is commonly depicted as a series of epithelial sheet folding events, this does not represent an empirically supported model. Here, we combine four-dimensional imaging with custom cell tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying OCM in zebrafish. Although cell division contributes to growth, we find it dispensable for eye formation. OCM depends instead on a complex set of cell movements coordinated between the prospective neural retina, retinal pigmented epithelium (RPE) and lens. Optic vesicle evagination persists for longer than expected; cells move in a pinwheel pattern during optic vesicle elongation and retinal precursors involute around the rim of the invaginating optic cup. We identify unanticipated movements, particularly of central and peripheral retina, RPE and lens. From cell tracking data, we generate retina, RPE and lens subdomain fate maps, which reveal novel adjacencies that might determine corresponding developmental signaling events. Finally, we find that similar movements also occur during chick eye morphogenesis, suggesting that the underlying choreography is conserved among vertebrates. 相似文献
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Takuma Kobayashi Kunio Yasuda Masasuke Araki 《Development, growth & differentiation》2009,51(8):723-733
Vertebrate ocular morphogenesis requires proper dorso‐ventral polarity within the optic vesicle, and loss of dorso‐ventral polarity results in failure of optic cup formation and domain specification, as shown by a reverse transplantation of the optic vesicle. We have shown previously that the ocular development depends not only on the signal within the antero‐ventral optic vesicle but also on the extraocular signals. In the present study, using embryonic transplantation of a discrete portion of the embryonic chick brain, we demonstrate formation of a second eye from the antero‐ventral hemicephalon when it was transplanted in the antero‐dorsal hemicephalon of the host embryo. The transplant consists of an antero‐ventral quadrant of the optic vesicle and the surrounding part of the anterior cephalon. The original dorso‐ventral polarity of the transplant was once cancelled and re‐established in accordance with that of the host embryo. Neither dorsal nor ventral cephalic halves in isolation did not develop into entire eye structures under the culture condition; the dorsal halves developed merely into the retinal pigmented epithelium and the ventral halves into the neural retina alone. The present study clearly suggests that extraocular dorsal and ventral signals counterbalance each other to specify the polarity of the optic vesicle. 相似文献
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Takuma Kobayashi Kunio Yasuda Masasuke Araki 《Development, growth & differentiation》2010,52(4):351-363
Dorsal and ventral specification in the early optic vesicle plays a crucial role in vertebrate ocular morphogenesis, and proper dorsal‐ventral polarity in the optic vesicle ensures that distinct structures develop in separate domains within the eye primordium. The polarity is determined progressively during development by coordinated regulation of extraocular dorsal and ventral factors. In the present study, we cultured discrete portions of embryonic chick brains by preparing anterior cephalon, anterior dorsal cephalon and anterior ventral cephalon, and clearly demonstrate that bone morphogenetic protein 4 (BMP4) and Sonic hedgehog (Shh) constitute a dorsal‐ventral signaling system together with fibroblast growth factor 8 (FGF8). BMP4 and Shh upregulate Tbx5 and Pax2, as reported previously, and at the same time Shh downregulates Tbx5, while BMP4 affects Pax2 expression to downregulate similarly. Shh induces Fgf8 expression in the ventral optic vesicle. This, in turn, determines the distinct boundary of the retinal pigmented epithelium and the neural retina by suppressing Mitf expression. The lens develops only when signals from both the dorsal and ventral regions come across together. Inverted deposition of Shh and BMP4 signals in organ‐cultured optic vesicle completely re‐organized ocular structures to be inverted. Based on these observations we propose a novel model in which the two signals govern the whole of ocular development when they encounter each other in the ocular morphogenic domain. 相似文献
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J S Taylor 《Development (Cambridge, England)》1987,99(3):393-410
This study concerns the retinotopic organization of the ganglion cell fibres in the visual system of the frog Xenopus laevis. HRP was used to trace the pathways taken by fibres from discrete retinal positions as they pass from the retina, along the optic nerve and into the chiasma. The ganglion cell fibres in the retina are arranged in fascicles which correspond with their circumferential positions of origin. Within the fascicles the fibres show little age-related layering and do not have a strict radial organization. As the fascicles of fibres pass into the optic nerve head there is some exchange of position resulting in some loss of the retinal circumferential organization. The poor radial organization of the fibres in the retinal fascicles persists as the fibres pass through the intraocular part of the nerve. At a position just behind the eye there is a major fibre reorganization in which fibres arising from cells of increasingly peripheral retinal locations are found to have passed into increasingly peripheral positions in the nerve. Thus, fibres from peripheral-most retina are located at the nerve perimeter, whilst fibres from central retina are located in the nerve core. It is at this point that the radial, chronotopic, ordering of the ganglion cell axons, found throughout the rest of the optic pathway, is established. This annular organization persists along the length of the nerve until a position just before the nerve enters the brain. Here, fibres from each annulus move to form layers as they pass into the optic chiasma. This change in the radial organization appears to be related to the pathway followed by all newly growing fibres, in the most superficial part of the optic tract, adjacent to the pia. Just behind the eye, where fibres become radially ordered, the circumferential organization of the projection is largely lost. Fibres from every circumferential retinal position, which are of similar radial position, are distributed within the same annulus of the nerve. At the nerve-chiasma junction where each annulus forms a single layer as it enters the optic tract, there is a further mixing of fibres from all circumferential positions. However, as the fibres pass through the chiasma some active pathway selection occurs, generating the circumferential organization of the fibres in the optic tract. Additional observations of the organization of fibres in the optic nerve of Rana pipiens confirm previous reports of a dual representation of fibres within the nerve. The difference in the organization of fibres in the optic nerve of Xenopus and Rana pipiens is discussed. 相似文献
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S Zhao F C Hung J S Colvin A White W Dai F J Lovicu D M Ornitz P A Overbeek 《Development (Cambridge, England)》2001,128(24):5051-5060
During vertebrate embryogenesis, the neuroectoderm differentiates into neural tissues and also into non-neural tissues such as the choroid plexus in the brain and the retinal pigment epithelium in the eye. The molecular mechanisms that pattern neural and non-neural tissues within the neuroectoderm remain unknown. We report that FGF9 is normally expressed in the distal region of the optic vesicle that is destined to become the neural retina, suggesting a role in neural patterning in the optic neuroepithelium. Ectopic expression of FGF9 in the proximal region of the optic vesicle extends neural differentiation into the presumptive retinal pigment epithelium, resulting in a duplicate neural retina in transgenic mice. Ectopic expression of constitutively active Ras is also sufficient to convert the retinal pigment epithelium to neural retina, suggesting that Ras-mediated signaling may be involved in neural differentiation in the immature optic vesicle. The original and the duplicate neural retinae differentiate and laminate with mirror-image polarity in the absence of an RPE, suggesting that the program of neuronal differentiation in the retina is autonomously regulated. In mouse embryos lacking FGF9, the retinal pigment epithelium extends into the presumptive neural retina, indicating a role of FGF9 in defining the boundary of the neural retina. 相似文献
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The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye 总被引:6,自引:0,他引:6
Bharti K Nguyen MT Skuntz S Bertuzzi S Arnheiter H 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2006,19(5):380-394
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A multitude of signalling pathways are involved in the process of forming an eye. Here we demonstrate that β-catenin is essential for eye development as inactivation of β-catenin prior to cellular specification in the optic vesicle caused anophthalmia in mice. By achieving this early and tissue-specific β-catenin inactivation we find that retinal pigment epithelium (RPE) commitment was blocked and eye development was arrested prior to optic cup formation due to a loss of canonical Wnt signalling in the dorsal optic vesicle. Thus, these results show that Wnt/β-catenin signalling is required earlier and play a more central role in eye development than previous studies have indicated. In our genetic model system a few RPE cells could escape β-catenin inactivation leading to the formation of a small optic rudiment. The optic rudiment contained several neural retinal cell classes surrounded by an RPE. Unlike the RPE cells, the neural retinal cells could be β-catenin-negative revealing that differentiation of the neural retinal cell classes is β-catenin-independent. Moreover, although dorsoventral patterning is initiated in the mutant optic vesicle, the neural retinal cells in the optic rudiment displayed almost exclusively ventral identity. Thus, β-catenin is required for optic cup formation, commitment to RPE cells and maintenance of dorsal identity of the retina. 相似文献
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Kagiyama Y Gotouda N Sakagami K Yasuda K Mochii M Araki M 《Development, growth & differentiation》2005,47(8):523-536
Dorsal-ventral (DV) specification in the early optic vesicle plays a crucial role in the proper development of the eye. To address the questions of how DV specification is determined and how it affects fate determination of the optic vesicle, isolated optic vesicles were cultured either in vitro or in ovo. The dorsal and ventral halves of the optic vesicle were fated to develop into retinal pigment epithelium (RPE) and neural retina, respectively, when they were separated from each other and cultured. In optic vesicles treated with collagenase to remove the surrounding tissues, the neuroepithelium gave rise to cRax expression but not Mitf, suggesting that surrounding tissues are necessary for RPE specification. This was also confirmed in in ovo explant cultures. Combination cultures of collagenase-treated optic vesicles with either the dorsal or ventral part of the head indicated that head-derived factors have an important role in the fate determination of the optic vesicle: in the optic vesicles co-cultured with the dorsal part of the head Mitf expression was induced in the neuroepithelium, while the ventral head portion did not have this effect. The dorsal head also suppressed Pax2 expression in the optic vesicle. These observations indicate that factors from the dorsal head portion have important roles in the establishment of DV polarity within the optic vesicle, which in turn induces the patterning and differentiation of the neural retina and pigment epithelium. 相似文献
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Barbara L. Gibsonm 《Journal of morphology》1984,181(2):205-220
Light and electron microscopic techniques show that the eye of the marine prosobranch gastropod, Ilyanassa obsoleta, is composed of an optic cavity, lens, cornea, retina, and neuropile, and is surrounded by a connective tissue capsule. The adult retina is a columnar epithelium containing three morphologically distinct cell types: photoreceptor, pigmented, and ciliated cells. The retina is continuous anteriorly with a cuboidal corneal epithelium. The neuropile, located immediately behind the retina, is composed of photoreceptor cell axons, accessory neurons, and their neurites. The embryonic eye is formed from surface ectoderm, which sinks inward as a pigmented cellular mass. At this time, the eye primordium already contains presumptive photoreceptor cells, pigmented retinal cells, and corneal cells. Several days later, just before hatching, the embryonic eye remains in intimate contact with the cerebral ganglion. It has no ciliated retinal cells, neuropile, optic nerve, or connective tissue capsule and its photoreceptor cells lack the electron-lucent vesicles and multivesicular bodies of adult photoreceptor cells. As the eye and the cerebral ganglion grow apart, the optic nerve, neuropile, and connective tissue capsule develop. 相似文献
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Zaghloul NA Yan B Moody SA 《Biology of the cell / under the auspices of the European Cell Biology Organization》2005,97(5):321-337
The specification of embryonic cells to produce the retina begins at early embryonic stages as a multi-step process that gradually restricts fate potentials. First, a subset of embryonic cells becomes competent to form retina by their lack of expression of endo-mesoderm-specifying genes. From these cells, a more restricted subset is biased to form retina by virtue of their close proximity to sources of bone morphogenetic protein antagonists during neural induction. During gastrulation, the definitive RSCs (retinal stem cells) are specified as the eye field by interactions with underlying mesoderm and the expression of a network of retina-specifying genes. As the eye field is transformed into the optic vesicle and optic cup, a heterogeneous population of RPCs (retinal progenitor cells) forms to give rise to the different domains of the retina: the optic stalk, retinal pigmented epithelium and neural retina. Further diversity of RPCs appears to occur under the influences of cell-cell interactions, cytokines and combinations of regulatory genes, leading to the differentiation of a multitude of different retinal cell types. This review examines what is known about each sequential step in retinal specification during normal vertebrate development, and how that knowledge will be important to understand how RSCs might be manipulated for regenerative therapies to treat retinal diseases. 相似文献
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The left eye was removed from Stage 56 Xenopus tadpoles. Two to 9 months after metamorphosis, electrophysiologic analysis showed that the surviving (right) eye mediated a normal visual field projection to the left (contralateral) optic tectum. In addition, a peripheral region of the same retina innervated the entire right (ipsilateral) tectum. Primary evidence that indicates this anomalous ipsilateral projection was due to direct retina-to-tectum innervation comes from singleunit analysis, latency measurements, and tectal lesion studies. Thus, the peripheral retina simultaneously connected in much different patterns to the two optic tecta, solely on the basis of the presence (in the left tectum) or absence (in the right tectum) of central retinal fibers. This documents a role for fiber-fiber interaction (such as repulsion or competition) acting in combination with fiber-tectum interactions in the formation of the retinotectal map. 相似文献
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Inbal Benhar Kitty Reemst Vyacheslav Kalchenko Michal Schwartz 《The EMBO journal》2016,35(11):1219-1235
The choroid plexus epithelium within the brain ventricles orchestrates blood‐derived monocyte entry to the central nervous system under injurious conditions, including when the primary injury site is remote from the brain. Here, we hypothesized that the retinal pigment epithelium (RPE) serves a parallel role, as a gateway for monocyte trafficking to the retina following direct or remote injury. We found elevated expression of genes encoding leukocyte trafficking determinants in mouse RPE as a consequence of retinal glutamate intoxication or optic nerve crush (ONC). Blocking VCAM‐1 after ONC interfered with monocyte infiltration into the retina and resulted in a local pro‐inflammatory cytokine bias. Live imaging of the injured eye showed monocyte accumulation first in the RPE, and subsequently in the retina, and peripheral leukocytes formed close contact with the RPE. Our findings further implied that the ocular milieu can confer monocytes a phenotype advantageous for neuroprotection. These results suggest that the eye utilizes a mechanism of crosstalk with the immune system similar to that of the brain, whereby epithelial barriers serve as gateways for leukocyte entry. 相似文献
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Hedgehog signalling maintains the optic stalk-retinal interface through the regulation of Vax gene activity 总被引:5,自引:0,他引:5
During early formation of the eye, the optic vesicle becomes partitioned into a proximal domain that forms the optic nerve and a distal domain that forms the retina. In this study, we investigate the activity of Nodal, Hedgehog (Hh) and Fgf signals and Vax family homeodomain proteins in this patterning event. We show that zebrafish vax1 and vax2 are expressed in overlapping domains encompassing the ventral retina, optic stalks and preoptic area. Abrogation of Vax1 and Vax2 activity leads to a failure to close the choroid fissure and progressive expansion of retinal tissue into the optic nerve, finally resulting in a fusion of retinal neurons and pigment epithelium with forebrain tissue. We show that Hh signals acting through Smoothened act downstream of the Nodal pathway to promote Vax gene expression. However, in the absence of both Nodal and Hh signals, Vax genes are expressed revealing that other signals, which we show include Fgfs, contribute to Vax gene regulation. Finally, we show that Pax2.1 and Vax1/Vax2 are likely to act in parallel downstream of Hh activity and that the bel locus (yet to be cloned) mediates the ability of Hh-, and perhaps Fgf-, signals to induce Vax expression in the preoptic area. Taking all these results together, we present a model of the partitioning of the optic vesicle along its proximo-distal axis. 相似文献