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Richard A. Lang - One of the best experts on this subject based on the ideXlab platform.
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a trio rhoa shroom3 pathway is required for apical constriction and epithelial invagination
Development, 2011Co-Authors: Timothy F Plageman, Bharesh K Chauhan, Fanny Jaudon, Xun Shang, Anne Debant, Christine Yang, Jeffrey D. Hildebrand, Yi Zheng, Richard A. LangAbstract:Epithelial invagination is a common feature of embryogenesis. An example of invagination morphogenesis occurs during development of the early eye when the Lens Placode forms the Lens pit. This morphogenesis is accompanied by a columnar-to-conical cell shape change (apical constriction or AC) and is known to be dependent on the cytoskeletal protein Shroom3. Because Shroom3-induced AC can be Rock1/2 dependent, we hypothesized that during Lens invagination, RhoA, Rock and a RhoA guanine nucleotide exchange factor (RhoA-GEF) would also be required. In this study, we show that Rock activity is required for Lens pit invagination and that RhoA activity is required for Shroom3-induced AC. We demonstrate that RhoA, when activated and targeted apically, is sufficient to induce AC and that RhoA plays a key role in Shroom3 apical localization. Furthermore, we identify Trio as a RhoA-GEF required for Shroom3-dependent AC in MDCK cells and in the Lens pit. Collectively, these data indicate that a Trio-RhoA-Shroom3 pathway is required for AC during Lens pit invagination.
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Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Bharesh K Chauhan, Yi Zheng, Ming Lou, Richard A. LangAbstract:Epithelial bending is a central feature of morphogenesis in animals. Here we show that mutual antagonism by the small Rho GTPases Rac1 and RhoA determines cell shape, tissue curvature, and invagination activity in the model epithelium of the developing mouse Lens. The epithelial cells of the invaginating Lens Placode normally elongate and change from a cylindrical to an apically constricted, conical shape. RhoA mutant Lens Placode cells are both longer and less apically constricted than control cells, thereby reducing epithelial curvature and invagination. By contrast, Rac1 mutant Lens Placode cells are shorter and more apically restricted than controls, resulting in increased epithelial curvature and precocious Lens vesicle closure. Quantification of RhoA- and Rac1-dependent pathway markers over the apical–basal axis of Lens pit cells showed that in RhoA mutant epithelial cells there was a Rac1 pathway gain of function and vice versa. These findings suggest that mutual antagonism produces balanced activities of RhoA-generated apical constriction and Rac1-dependent cell elongation that controls cell shape and thus curvature of the invaginating epithelium. The ubiquity of the Rho family GTPases suggests that these mechanisms are likely to apply generally where epithelial morphogenesis occurs.
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pax6 dependent shroom3 expression regulates apical constriction during Lens Placode invagination
Development, 2010Co-Authors: Timothy F Plageman, Mei I Chung, April N. Smith, Richard A. Lang, Jeffrey D. Hildebrand, John B WallingfordAbstract:Embryonic development requires a complex series of relative cellular movements and shape changes that are generally referred to as morphogenesis. Although some of the mechanisms underlying morphogenesis have been identified, the process is still poorly understood. Here, we address mechanisms of epithelial morphogenesis using the vertebrate Lens as a model system. We show that the apical constriction of Lens epithelial cells that accompanies invagination of the Lens Placode is dependent on Shroom3, a molecule previously associated with apical constriction during morphogenesis of the neural plate. We show that Shroom3 is required for the apical localization of F-actin and myosin II, both crucial components of the contractile complexes required for apical constriction, and for the apical localization of Vasp, a Mena family protein with F-actin anti-capping function that is also required for morphogenesis. Finally, we show that the expression of Shroom3 is dependent on the crucial Lens-induction transcription factor Pax6. This provides a previously missing link between Lens-induction pathways and the morphogenesis machinery and partly explains the absence of Lens morphogenesis in Pax6-deficient mutants.
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Cdc42- and IRSp53-dependent contractile filopodia tether presumptive Lens and retina to coordinate epithelial invagination.
Development (Cambridge England), 2009Co-Authors: Bharesh K Chauhan, Yi Zheng, Sonya C. Faber, Ming Lou, Andrea Disanza, Sue-yeon Choi, Hilary E. Beggs, Giorgio Scita, Richard A. LangAbstract:The vertebrate Lens provides an excellent model with which to study the mechanisms required for epithelial invagination. In the mouse, the Lens forms from the head surface ectoderm. A domain of ectoderm first thickens to form the Lens Placode and then invaginates to form the Lens pit. The epithelium of the Lens Placode remains in close apposition to the epithelium of the presumptive retina as these structures undergo a coordinated invagination. Here, we show that F-actin-rich basal filopodia that link adjacent presumptive Lens and retinal epithelia function as physical tethers that coordinate invagination. The filopodia, most of which originate in the presumptive Lens, form at E9.5 when presumptive Lens and retinal epithelia first come into close contact, and have retracted by E11.5 when invagination is complete. At E10.5 - the Lens pit stage - there is approximately one filopodium per epithelial cell. Formation of filopodia is dependent on the Rho family GTPase Cdc42 and the Cdc42 effector IRSp53 (Baiap2). Loss of filopodia results in reduced Lens pit invagination. Pharmacological manipulation of the actin-myosin contraction pathway showed that the filopodia can respond rapidly in length to change inter-epithelial distance. These data suggest that the Lens-retina inter-epithelial filopodia are a fine-tuning mechanism to assist in Lens pit invagination by transmitting the forces between presumptive Lens and retina. Although invagination of the archenteron in sea urchins and dorsal closure in Drosophila are known to be partly dependent on filopodia, this mechanism of morphogenesis has not previously been identified in vertebrates.
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The upstream ectoderm enhancer in Pax6 has an important role in Lens induction.
Development (Cambridge England), 2001Co-Authors: Patricia Dimanlig, Sonya C. Faber, Woytek Auerbach, Helen P. Makarenkova, Richard A. LangAbstract:The Pax6 gene has a central role in development of the eye. We show, through targeted deletion in the mouse, that an ectoderm enhancer in the Pax6 gene is required for normal Lens formation. Ectoderm enhancer-deficient embryos exhibit distinctive defects at every stage of Lens development. These include a thinner Lens Placode, reduced placodal cell proliferation, and a small Lens pit and Lens vesicle. In addition, the Lens vesicle fails to separate from the surface ectoderm and the maturing Lens is smaller and shows a delay in fiber cell differentiation. Interestingly, deletion of the ectoderm enhancer does not eliminate Pax6 production in the Lens Placode but results in a diminished level that, in central sections, is apparent primarily on the nasal side. This argues that Pax6 expression in the Lens Placode is controlled by the ectoderm enhancer and at least one other transcriptional control element. It also suggests that Pax6 enhancers active in the Lens Placode drive expression in distinct subdomains, an assertion that is supported by the expression pattern of a lacZ reporter transgene driven by the ectoderm enhancer. Interestingly, deletion of the ectoderm enhancer causes loss of expression of Foxe3, a transcription factor gene mutated in the dysgenetic Lens mouse. When combined, these data and previously published work allow us to assemble a more complete genetic pathway describing Lens induction. This pathway features (1) a pre-placodal phase of Pax6 expression that is required for the activity of multiple, downstream Pax6 enhancers; (2) a later, placodal phase of Pax6 expression regulated by multiple enhancers; and (3) the Foxe3 gene in a downstream position. This pathway forms a basis for future analysis of Lens induction mechanism.
Nadean L. Brown - One of the best experts on this subject based on the ideXlab platform.
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requirements for jag1 rbpj mediated notch signaling during early mouse Lens development
Developmental Dynamics, 2012Co-Authors: Tien T Le, Kevin W. Conley, Timothy J. Mead, Sheldon Rowan, Katherine E. Yutzey, Nadean L. BrownAbstract:Background: During vertebrate Lens development, the Lens Placode in the embryonic ectoderm invaginates into a Lens vesicle, which then separates from the surface epithelium, followed by two waves of fiber cell differentiation. In the mouse, multiple labs have shown that Jag1-Notch signaling is critically required during the second wave of Lens fiber cell formation. However, Notch signaling appears to play no obvious role during Lens induction or morphogenesis, although multiple pathway genes are expressed at these earlier stages. Results: Here, we explored functions for Notch signaling specifically during early Lens development, by using the early-acting AP2α-Cre driver to delete Jag1 or Rbpj. We found that Jag1 and Rbpj are not required during Lens induction, but are necessary for proper Lens vesicle separation from the surface ectoderm. Conclusions: We conclude that precise levels of Notch signaling are essential during Lens vesicle morphogenesis. In addition, AP2α-Cre-mediated deletion of Rbpj resulted in embryos with cardiac outflow tract and liver deformities, and perinatal lethality. Developmental Dynamics 241:493–504, 2012. © 2012 Wiley Periodicals, Inc.
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Requirements for Jag1-Rbpj mediated Notch signaling during early Lens development
Developmental Biology, 2011Co-Authors: Tien Le, Kevin W. Conley, Timothy J. Mead, Sheldon Rowan, Katherine E. Yutzey, Nadean L. BrownAbstract:During vertebrate Lens development the Lens Placode in the embryonic ectoderm invaginates into a Lens vesicle, which then separates from the surface epithelium, followed by two waves of fiber cell differentiation. In the mouse, multiple labs have shown that Jag1-Notch signaling is critically required during the second wave of Lens fiber cell formation. However, Notch signaling appears to play no obvious role during Lens induction or morphogenesis, although multiple pathway genes are expressed at these earlier stages. Here we explored functions for Notch signaling specifically during early Lens development, by using the early-acting AP2α-Cre driver to delete Jag1 or Rbpj. We found that Jag1 and Rbpj are not required during Lens induction, but are necessary for proper Lens vesicle separation from the surface ectoderm. We conclude that precise levels of Notch signaling are essential during Lens vesicle morphogenesis. In addition, AP2α-Cre-mediated deletion of Rbpj resulted in embryos with cardiac outflow tract and liver deformities, and perinatal lethality.
Timothy F Plageman - One of the best experts on this subject based on the ideXlab platform.
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Formation and contraction of multicellular actomyosin cables facilitate Lens Placode invagination.
Developmental biology, 2020Co-Authors: Nathalie S. Houssin, Jessica B. Martin, Vincenzo Coppola, Sung Ok Yoon, Timothy F PlagemanAbstract:Abstract Embryonic morphogenesis relies on the intrinsic ability of cells, often through remodeling the cytoskeleton, to shape epithelial tissues during development. Epithelial invagination is an example of morphogenesis that depends on this remodeling but the cellular mechanisms driving arrangement of cytoskeletal elements needed for tissue deformation remain incompletely characterized. To elucidate these mechanisms, live fluorescent microscopy and immunohistochemistry on fixed specimens were performed on chick and mouse Lens Placodes. This analysis revealed the formation of peripherally localized, circumferentially orientated and aligned junctions enriched in F-actin and MyoIIB. Once formed, the aligned junctions contract in a Rho-kinase and non-muscle myosin dependent manner. Further molecular characterization of these junctions revealed a Rho-kinase dependent accumulation of Arhgef11, a RhoA-specific guanine exchange factor known to regulate the formation of actomyosin cables and junctional contraction. In contrast, the localization of the Par-complex protein Par3, was reduced in these circumferentially orientated junctions. In an effort to determine if Par3 plays a negative role in MyoIIB accumulation, Par3-deficient mouse embryos were analyzed which not only revealed an increase in bicellular junctional accumulation of MyoIIB, but also a reduction of Arhgef11. Together, these results highlight the importance of the formation of the multicellular actomyosin cables that appear essential to the initiation of epithelial invagination and implicate the potential role of Arhgef11 and Par3 in their contraction and formation.
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Lens Placode planar cell polarity is dependent on Cdc42-mediated junctional contraction inhibition
Developmental biology, 2016Co-Authors: Maria Muccioli, Dalya Qaisi, Ken Herman, Timothy F PlagemanAbstract:Development of the ocular Lens commences with the formation of the Lens Placode, an epithelial structure that thickens and subsequently bends inward in a process called invagination. Invagination is observed during the development of many embryonic structures, but the spectrum of morphogenetic events driving this process are, in most cases, not fully understood. A characteristic commonly found in embryonic tissues undergoing epithelial reorganization is planar polarity, a property where cells are geometrically and/or molecularly orientated in a specific direction along the plane of an epithelium. Planar polarity is known to drive the morphogenesis of several epithelial structures, however its role during invagination events is less clear. We have found that at the onset of invagination, cells of the Lens Placode become geometrically planar polarized such that they are orientated toward a central point in the Lens Placode. Further investigation revealed that this is due to contraction of radially orientated junctions and the elongation of those circumferentially orientated. Radial junctions have an elevated localization of actomyosin and their contraction is dependent on the F-actin and Rho-kinase binding protein, Shroom3. Elongation of circumferential junctions is dependent upon Cdc42, a Rho-GTPase known to regulate polarity via the Par-complex. We determined that Cdc42 and members of the Par-complex inhibit Shroom3-induced contractility and promote anisotropic Placode cell geometry through inhibition of junctional contraction. We postulate that invagination of the Lens Placode requires careful orchestration of these opposing processes which are mediated by the planar polarization of junctional proteins.
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a trio rhoa shroom3 pathway is required for apical constriction and epithelial invagination
Development, 2011Co-Authors: Timothy F Plageman, Bharesh K Chauhan, Fanny Jaudon, Xun Shang, Anne Debant, Christine Yang, Jeffrey D. Hildebrand, Yi Zheng, Richard A. LangAbstract:Epithelial invagination is a common feature of embryogenesis. An example of invagination morphogenesis occurs during development of the early eye when the Lens Placode forms the Lens pit. This morphogenesis is accompanied by a columnar-to-conical cell shape change (apical constriction or AC) and is known to be dependent on the cytoskeletal protein Shroom3. Because Shroom3-induced AC can be Rock1/2 dependent, we hypothesized that during Lens invagination, RhoA, Rock and a RhoA guanine nucleotide exchange factor (RhoA-GEF) would also be required. In this study, we show that Rock activity is required for Lens pit invagination and that RhoA activity is required for Shroom3-induced AC. We demonstrate that RhoA, when activated and targeted apically, is sufficient to induce AC and that RhoA plays a key role in Shroom3 apical localization. Furthermore, we identify Trio as a RhoA-GEF required for Shroom3-dependent AC in MDCK cells and in the Lens pit. Collectively, these data indicate that a Trio-RhoA-Shroom3 pathway is required for AC during Lens pit invagination.
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pax6 dependent shroom3 expression regulates apical constriction during Lens Placode invagination
Development, 2010Co-Authors: Timothy F Plageman, Mei I Chung, April N. Smith, Richard A. Lang, Jeffrey D. Hildebrand, John B WallingfordAbstract:Embryonic development requires a complex series of relative cellular movements and shape changes that are generally referred to as morphogenesis. Although some of the mechanisms underlying morphogenesis have been identified, the process is still poorly understood. Here, we address mechanisms of epithelial morphogenesis using the vertebrate Lens as a model system. We show that the apical constriction of Lens epithelial cells that accompanies invagination of the Lens Placode is dependent on Shroom3, a molecule previously associated with apical constriction during morphogenesis of the neural plate. We show that Shroom3 is required for the apical localization of F-actin and myosin II, both crucial components of the contractile complexes required for apical constriction, and for the apical localization of Vasp, a Mena family protein with F-actin anti-capping function that is also required for morphogenesis. Finally, we show that the expression of Shroom3 is dependent on the crucial Lens-induction transcription factor Pax6. This provides a previously missing link between Lens-induction pathways and the morphogenesis machinery and partly explains the absence of Lens morphogenesis in Pax6-deficient mutants.
P Bovolenta - One of the best experts on this subject based on the ideXlab platform.
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Six9 (Optx2), a new member of the six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development.
Mechanisms of development, 1999Co-Authors: J López-ríos, M E Gallardo, S Rodriguez De Córdoba, P BovolentaAbstract:The Drosophila gene sine oculis (so) is a nuclear homeoprotein, which is required for eye development. Several homologues of so have been found in vertebrates. We report here a detailed expression analysis in chick and mouse of Six9 (Optx2), a novel gene of the Six/sine oculis family closely related to Six3. Six9 (Optx2) is first expressed at presomitic stages in the head-fold, both in the neural plate and in the underlying axial mesoderm. Thereafter, Six9 (Optx2) is strongly expressed in the presumptive and differentiating neural retina and ventral optic stalk, in the olfactory Placodes, in the hypothalamus and in the pituitary gland. This expression pattern largely overlaps with that of Six3, but several differences exist between the expression domain of the two genes. At presomitic stages, the posterior boundary of Six3 expression is at the same axial level both in the prechordal plate and in the overlying neural plate. In contrast, Six9 (Optx2) expression in the prechordal plate extends more caudal to that of the neural plate, occupying a more restricted V-shaped territory. Similarly, during the early events of eye patterning, Six3 is first expressed in the entire optic vesicle and Lens Placode. Only later does its expression become confined to the prospective and differentiating neural retina. Conversely, Six9 (Optx2) is never observed in the Lens Placode of either chick and mouse, and from early stages of optic vesicle development, Six9 (Optx2) transcripts are restrained to the prospective ventral neural retina and optic stalks.
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Expression pattern of cSix3, a member of the Six/sine oculis family of transcription factors.
Mechanisms of development, 1998Co-Authors: P Bovolenta, A Mallamaci, L Puelles, E BoncinelliAbstract:We describe the expression pattern of cSix3, a chick homologue of the murine Six3. cSix3 transcripts are expressed from presomitic stages in the most anterior portion of the neural plate. As the neural tube folds and the optic vesicles evaginate, cSix3 is expressed in the optic vesicle and the rostroventral forebrain. At later stages, cSix3 is found in most of the structures derived from the anterior neural plate, i.e. olfactory epithelium, septum, adenohypophysis, hypothalamus and preoptic areas. During eye development, cSix3 expression is first found in the entire optic vesicle and the overlying ectoderm but soon becomes restricted to the prospective neural retina and to the Lens Placode. In the developing neural retina, cSix3 is expressed in the entire undifferentiated neuroepithelium but is rapidly downregulated, first in the postmitotic photoreceptors and later in the majority of retinal ganglion cells.
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Gene expression pattern Expression pattern of cSix3, a member of the Six/sine oculis family of transcription factors
1998Co-Authors: P Bovolenta, A Mallamaci, L Puelles, E BoncinelliAbstract:We describe the expression pattern of cSix3, a chick homologue of the murine Six3. cSix3 transcripts are expressed from presomitic stages in the most anterior portion of the neural plate. As the neural tube folds and the optic vesicles evaginate, cSix3 is expressed in the optic vesicle and the rostroventral forebrain. At later stages, cSix3 is found in most of the structures derived from the anterior neural plate, i.e. olfactory epithelium, septum, adenohypophysis, hypothalamus and preoptic areas. During eye development, cSix3 expression is first found in the entire optic vesicle and the overlying ectoderm but soon becomes restricted to the prospective neural retina and to the Lens Placode. In the developing neural retina, cSix3 is expressed in the entire undifferentiated neuroepithelium but is rapidly downregulated, first in the postmitotic photoreceptors and later in the majority of retinal ganglion cells. © 1998 Elsevier Science Ireland Ltd.
Thomas Hollemann - One of the best experts on this subject based on the ideXlab platform.
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Olfactory and Lens Placode formation is controlled by the hedgehog-interacting protein (Xhip) in Xenopus.
Developmental biology, 2005Co-Authors: Yvonne Cornesse, Tomas Pieler, Thomas HollemannAbstract:The integration of multiple signaling pathways is a key issue in several aspects of embryonic development. In this context, extracellular inhibitors of secreted growth factors play an important role, which is to antagonize specifically the activity of the corresponding signaling molecule. We provide evidence that the Hedgehog-interacting protein (Hip) from Xenopus, previously described as a Hedgehog-specific antagonist in the mouse, interferes with Wnt-8 and eFgf/Fgf-8 signaling pathways as well. To address the function of Hip during early embryonic development, we performed gain- and loss-of-function studies in the frog. Overexpression of Xhip or mHip1 resulted in a dramatic increase of retinal structures and larger olfactory Placodes primarily at the expense of other brain tissues. Furthermore, loss of Xhip function resulted in a suppression of olfactory and Lens Placode formation. Therefore, the localized expression of Xhip may counteract certain overlapping signaling activities, which inhibit the induction of distinct sensory Placodes.
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Xpitx-1: a homeobox gene expressed during pituitary and cement gland formation of Xenopus embryos.
Mechanisms of Development, 1999Co-Authors: Thomas Hollemann, Tomas PielerAbstract:Pitx-1 is a member of the family of bicoid-related vertebrate homeobox genes; it was originally identified as a tissue-specific transcriptional regulator of the proopiomelacortin gene. Here we report on the embryonic expression of Xpitx-1, which is expressed in the anterior neural ridge and in the cement gland Anlage during late gastrulation/early neurulation. In tadpole stage embryos Xpitx-1 transcripts are primarily detected in the cement gland, stomodeal-hypophyseal Anlage, oral epithelia and Lens Placode. Therefore, Xpitx-1 may be part of the genetic network that controls the early development of these structures.
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Gene expression pattern Xpitx-1: a homeobox gene expressed during pituitary and cement gland formation of Xenopus embryos
1999Co-Authors: Thomas Hollemann, Tomas PielerAbstract:Pitx-1 is a member of the family of bicoid-related vertebrate homeobox genes; it was originally identified as a tissue-specific transcriptional regulator of the proopiomelacortin gene. Here we report on the embryonic expression of Xpitx-1, which is expressed in the anterior neural ridge and in the cement gland Anlage during late gastrulation/early neurulation. In tadpole stage embryos Xpitx-1 transcripts are primarily detected in the cement gland, stomodeal-hypophyseal Anlage, oral epithelia and Lens Placode. Therefore, Xpitx-1 may be part of the genetic network that controls the early development of these structures. q 1999 Elsevier Science Ireland Ltd. All rights reserved.