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Stephen W. Wilson - One of the best experts on this subject based on the ideXlab platform.
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Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the Optic vesicle.
Nature communications, 2014Co-Authors: Marcos Julián Cardozo, Luisa Sánchez-arrones, África Sandonís, Cristina Sánchez-camacho, Gaia Gestri, Stephen W. Wilson, Isabel Guerrero, Paola BovolentaAbstract:Patterning of the vertebrate Optic vesicle into proximal/Optic Stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes Stalk specification. In the absence of Hh signalling, the Stalks are not specified, causing cyclopia. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc1). This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Here we show that in the developing zebrafish and chick Optic vesicle, in which cdon and ptc1 are expressed with a complementary pattern, Cdon acts as a negative Hh signalling regulator. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion. This Ptc-independent function protects the retinal primordium from Hh activity, defines the Stalk/retina boundary and thus the correct proximo-distal patterning of the eye.
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London NW7 1AA
2013Co-Authors: Ichiro Masai, Derek L. Stemple, Hitoshi Okamoto, Stephen W. WilsonAbstract:In zebrafish, neuronal differentiation progresses across the retina in a pattern that is reminiscent of the neuro-genic wave that sweeps across the developing eye in Drosophila. We show that expression of a zebrafish homolog of Drosophila atonal, ath5, sweeps across the eye predicting the wave of neuronal differentiation. By analyzing the regulation of ath5 expression, we have elucidated the mechanisms that regulate initiation and spread of neurogenesis in the retina. ath5 expression is lost in Nodal pathway mutant embryos lacking axial tissues that include the prechordal plate. A likely role for axial tissue is to induce Optic Stalk cells that subsequently regulate ath5 expression. Our results suggest that a series of inductive events, initiated from the prechordal plate and progressing from the Optic Stalks, regulates the spread of neuronal dif-ferentiation across the zebrafish retina
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retinoic acid receptor signaling regulates choroid fissure closure through independent mechanisms in the ventral Optic cup and periocular mesenchyme
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Giuseppe Lupo, Roshantha A S Chandraratna, Gaia Gestri, Matthew Obrien, Ross M Denton, Steven V Ley, William A Harris, Stephen W. WilsonAbstract:Retinoic acid receptor (RAR) signaling is required for morphogenesis of the ventral Optic cup and closure of the choroid fissure, but the mechanisms by which this pathway regulates ventral eye development remain controversial and poorly understood. Although previous studies have implicated neural crest-derived periocular mesenchyme (POM) as the critical target of RA action in the eye, we show here that RAR signaling regulates choroid fissure closure in zebrafish by acting on both the ventral Optic cup and the POM. We describe RAR-dependent regulation of eight genes in the neuroepithelial cells of the ventral retina and Optic Stalk and of six genes in the POM and show that these ventral retina/Optic Stalk and POM genes function independently of each other. Consequently, RAR signaling regulates ventral eye development through two independent, nonredundant mechanisms in different ocular tissues. Furthermore, the identification of two cohorts of genes implicated in ventral eye morphogenesis may help to elucidate the genetic basis of ocular coloboma in humans.
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hedgehog signalling maintains the Optic Stalk retinal interface through the regulation of vax gene activity
Development, 2003Co-Authors: Masaya Takeuchi, Jonathan D W Clarke, Stephen W. WilsonAbstract: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.
Giuseppe Lupo - One of the best experts on this subject based on the ideXlab platform.
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dorsoventral patterning of the xenopus eye involves differential temporal changes in the response of Optic Stalk and retinal progenitors to hh signalling
Neural Development, 2015Co-Authors: Xiumei Wang, Giuseppe Lupo, William A Harris, Giuseppina Barsacchi, Ying LiuAbstract:Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting Optic Stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals. In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During Optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate Optic Stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the Optic Stalk, while the effects of Hh inhibition during Optic vesicle stages were limited to the reduction of Optic Stalk size. Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the Optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of Optic Stalk, ventral retina and dorsal retinal domains. In the second window, between Optic vesicle and Optic cup stages, this pathway plays a more limited role in the maintenance of the Optic Stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.
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retinoic acid receptor signaling regulates choroid fissure closure through independent mechanisms in the ventral Optic cup and periocular mesenchyme
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Giuseppe Lupo, Roshantha A S Chandraratna, Gaia Gestri, Matthew Obrien, Ross M Denton, Steven V Ley, William A Harris, Stephen W. WilsonAbstract:Retinoic acid receptor (RAR) signaling is required for morphogenesis of the ventral Optic cup and closure of the choroid fissure, but the mechanisms by which this pathway regulates ventral eye development remain controversial and poorly understood. Although previous studies have implicated neural crest-derived periocular mesenchyme (POM) as the critical target of RA action in the eye, we show here that RAR signaling regulates choroid fissure closure in zebrafish by acting on both the ventral Optic cup and the POM. We describe RAR-dependent regulation of eight genes in the neuroepithelial cells of the ventral retina and Optic Stalk and of six genes in the POM and show that these ventral retina/Optic Stalk and POM genes function independently of each other. Consequently, RAR signaling regulates ventral eye development through two independent, nonredundant mechanisms in different ocular tissues. Furthermore, the identification of two cohorts of genes implicated in ventral eye morphogenesis may help to elucidate the genetic basis of ocular coloboma in humans.
Stephan Heermann - One of the best experts on this subject based on the ideXlab platform.
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morphogenesis and axis specification occur in parallel during Optic cup and Optic fissure formation differentially modulated by bmp and wnt
Open Biology, 2019Co-Authors: Priska Eckert, Max D. Knickmeyer, Lucas Schütz, Joachim Wittbrodt, Stephan HeermannAbstract:Optic cup morphogenesis is an intricate process. Especially, the formation of the Optic fissure is not well understood. Persisting Optic fissures, termed coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most acknowledged reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate Optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the Optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the Optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the Optic Stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the Optic Stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the Optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal-ventral Optic cup domains.
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Supplemental Movie 18.avi from Morphogenesis and axis specification occur in parallel during Optic cup and Optic fissure formation, differentially modulated by BMP and Wnt
2019Co-Authors: Priska Eckert, Max D. Knickmeyer, Lucas Schütz, Joachim Wittbrodt, Stephan HeermannAbstract:Optic cup morphogenesis is an intricate process. Especially, the formation of the Optic fissure is not well understood. Persisting Optic fissures, coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most appreciated reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate Optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the Optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the Optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the Optic Stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the Optic Stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the Optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal–ventral Optic cup domains
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Supplemental Movie 12.avi from Morphogenesis and axis specification occur in parallel during Optic cup and Optic fissure formation, differentially modulated by BMP and Wnt
2019Co-Authors: Priska Eckert, Max D. Knickmeyer, Lucas Schütz, Joachim Wittbrodt, Stephan HeermannAbstract:Optic cup morphogenesis is an intricate process. Especially, the formation of the Optic fissure is not well understood. Persisting Optic fissures, coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most appreciated reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate Optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the Optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the Optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the Optic Stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the Optic Stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the Optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal–ventral Optic cup domains
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Revision Figure 5 supplement Eckert et al 2018 upload.pdf from Morphogenesis and axis specification occur in parallel during Optic cup and Optic fissure formation, differentially modulated by BMP and Wnt
2019Co-Authors: Priska Eckert, Max D. Knickmeyer, Lucas Schütz, Joachim Wittbrodt, Stephan HeermannAbstract:Optic cup morphogenesis is an intricate process. Especially, the formation of the Optic fissure is not well understood. Persisting Optic fissures, coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most appreciated reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate Optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the Optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the Optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the Optic Stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the Optic Stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the Optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal–ventral Optic cup domains
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Supplemental Movie 17.avi from Morphogenesis and axis specification occur in parallel during Optic cup and Optic fissure formation, differentially modulated by BMP and Wnt
2019Co-Authors: Priska Eckert, Max D. Knickmeyer, Lucas Schütz, Joachim Wittbrodt, Stephan HeermannAbstract:Optic cup morphogenesis is an intricate process. Especially, the formation of the Optic fissure is not well understood. Persisting Optic fissures, coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most appreciated reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate Optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the Optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the Optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the Optic Stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the Optic Stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the Optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal–ventral Optic cup domains
Peter Gruss - One of the best experts on this subject based on the ideXlab platform.
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retinal pigmented epithelium determination requires the redundant activities of pax2 and pax6
Development, 2003Co-Authors: Nicole Bäumer, Till Marquardt, Anastassia Stoykova, Dieter Treichel, Ruth Asherypadan, Derek Spieler, Peter GrussAbstract:The transcription factors Pax2 and Pax6 are co-expressed in the entire Optic vesicle (OV) prior and concomitant with the establishment of distinct neuroretinal, retinal, pigmented-epithelial and Optic-Stalk progenitor domains, suggesting redundant functions during retinal determination. Pax2; Pax6 compound mutants display a dose-dependent reduction in the expression of the melanocyte determinant Mitf, accompanied by transdifferentiation of retinal pigmented epithelium (RPE) into neuroretina (NR) in Pax2 -/- ; Pax6 +/- embryos, which strongly resembles the phenotype of Mitf -null mutants. In Pax2 -/- ; Pax6 -/- OVs Mitf fails to be expressed and NR markers occupy the area that usually represents the Mitf + RPE domain. Furthermore, both, Pax2 and Pax6 bind to and activate a MITF RPE - promoter element in vitro, whereas prolonged expression of Pax6 in the Pax2-positive Optic Stalk leads to ectopic Mitf expression and RPE differentiation in vivo. Together, these results demonstrate that the redundant activities of Pax2 and Pax6 direct the determination of RPE, potentially by directly controlling the expression of RPE determinants.
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spatial specification of mammalian eye territories by reciprocal transcriptional repression of pax2 and pax6
Development, 2000Co-Authors: Martin K. Schwarz, Nicole Andrejewski, Birgitta Kammandel, Gilbert Bernier, Francesco Cecconi, Martin Wagner, Peter GrussAbstract:We have studied the molecular basis of the Pax2 and Pax6 function in the establishment of visual system territories. Loss-of-function mutants have revealed crucial roles for Pax2 in the generation of the Optic Stalk and for Pax6 in the development of the Optic cup. Ectopic expression of Pax6 in the Optic Stalk under control of Pax2 promoter elements resulted in a shift of the Optic cup/Optic Stalk boundary indicated by the presence of retinal pigmented cells on the Optic Stalk. By studying mouse embryos at early developmental stages we detected an expansion of Pax2 expression domain in the Pax6(−/−) mutant and of Pax6 expression domain in the Pax2(−/−) embryo. These results suggest that the position of the Optic cup/Optic Stalk boundary depends on Pax2 and Pax6 expression, hinting at a possible molecular interaction. Using gel shift experiments, we confirmed the presence of Pax2- and Pax6-binding sites on the retina enhancer of the Pax6 gene and on the Pax2 upstream control region, respectively. Co-transfection experiments revealed a reciprocal inhibition of Pax2 promoter/enhancer activity by Pax6 protein and vice versa. Based on our findings, we propose a model for Pax gene regulation that establishes the proper spatial regionalization of the mammalian visual system.
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six6 optx2 is a novel murine six3 related homeobox gene that demarcates the presumptive pituitary hypothalamic axis and the ventral Optic Stalk
Mechanisms of Development, 1999Co-Authors: D Jean, G Bernier, Peter GrussAbstract:We report on the isolation of a murine homeobox-containing gene, Six6 (Optx2), that shows extended identity in its coding region with Six3, the only member of the mammalian Six gene family known to be expressed in the Optic primordium. Phylogenetic analysis demonstrates that Six6 and Six3 belong to a separate group of homeobox-genes that are closely related to the recently identified Drosophila optix. Earliest Six6 expression was detected in the floor of the diencephalic portion of the primitive forebrain, a region predicted to give rise to the neurohypophysis and to the hypothalamus. Later on, Six6 mRNA was found in the primordial tissues giving rise to the mature pituitary: the Rathke’s pouch and the infundibular recess. In the Optic primordium, Six6 demarcates the presumptive ventral Optic Stalk and the ventral portion of the future neural retina. In the developing eye, Six6 expression was detected in the neural retina, the Optic chiasma and Optic Stalk, but not in the lens. When compared to Six6, Six3 expression pattern was highly similar, but with a generally broader transcripts distribution in the brain and in the visual system. We finally show that Six6 does not require Pax6 for its expression in the Optic primordium, suggesting that Six6 acts on a parallel and/or independent pathway with Pax6 in the genetic cascade governing early development of the eye. q 1999 Elsevier Science Ireland Ltd. All rights reserved.
Monika Stengl - One of the best experts on this subject based on the ideXlab platform.
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Optic lobe commissures in a three dimensional brain model of the cockroach leucophaea maderae a search for the circadian coupling pathways
The Journal of Comparative Neurology, 2002Co-Authors: Thomas Reischig, Monika StenglAbstract:The circadian rhythm of locomotor activity in the cockroach Leucophaea maderae is controlled by bilaterally symmetric, apparently directly coupled, circadian pacemakers in the Optic lobes. Strong evidence predicts that ventromedial to the medulla, the accessory medulla with associated pigment-dispersing hormone-immunoreactive neurons is this circadian clock. In search for direct coupling pathways between both clocks, we performed horseradish peroxidase backfills from one Optic Stalk as well as dextran and horseradish peroxidase injections into one accessory medulla. Seven commissures with projections in the contralateral Optic lobe were identified and reconstructed. Three of these commissures connected both accessory medullae. Two of these resembled the arborization pattern of the pigment-dispersing hormone-immunoreactive neurons, which are circadian pacemaker candidates in insects. This finding suggests that some of these pacemaker candidates form a direct circadian coupling pathway. For better visualization of reconstructed commissures, we implemented the reconstructions into a three-dimensional model of the cockroach brain. J. Comp. Neurol. 443:388–400, 2002. © 2002 Wiley-Liss, Inc.
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Optic lobe commissures in a three dimensional brain model of the cockroach leucophaea maderae a search for the circadian coupling pathways
The Journal of Comparative Neurology, 2002Co-Authors: Thomas Reischig, Monika StenglAbstract:The circadian rhythm of locomotor activity in the cockroach Leucophaea maderae is controlled by bilaterally symmetric, apparently directly coupled, circadian pacemakers in the Optic lobes. Strong evidence predicts that ventromedial to the medulla, the accessory medulla with associated pigment-dispersing hormone-immunoreactive neurons is this circadian clock. In search for direct coupling pathways between both clocks, we performed horseradish peroxidase backfills from one Optic Stalk as well as dextran and horseradish peroxidase injections into one accessory medulla. Seven commissures with projections in the contralateral Optic lobe were identified and reconstructed. Three of these commissures connected both accessory medullae. Two of these resembled the arborization pattern of the pigment-dispersing hormone-immunoreactive neurons, which are circadian pacemaker candidates in insects. This finding suggests that some of these pacemaker candidates form a direct circadian coupling pathway. For better visualization of reconstructed commissures, we implemented the reconstructions into a three-dimensional model of the cockroach brain.