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Patrick Charnay - One of the best experts on this subject based on the ideXlab platform.
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Krox20 hindbrain regulation incorporates multiple modes of cooperation between cis-acting elements
PLoS Genetics, 2017Co-Authors: Elodie Thierion, Patrick Charnay, Johan Le Men, Samuel Collombet, Céline Hernandez, Fanny Coulpier, Patrick Torbey, Morgane Thomas-chollier, Daan Noordermeer, Pascale Gilardi-hebenstreitAbstract:Developmental genes can harbour multiple transcriptional enhancers that act simultaneously or in succession to achieve robust and precise spatiotemporal expression. However, the mechanisms underlying cooperation between cis-acting elements are poorly documented, notably in vertebrates. The mouse gene Krox20 encodes a transcription factor required for the specification of two segments (Rhombomeres) of the developing hindbrain. In Rhombomere 3, Krox20 is subject to direct positive feedback governed by an autoregulatory enhancer, element A. In contrast, a second enhancer, element C, distant by 70 kb, is active from the initiation of transcription independent of the presence of the KROX20 protein. Here, using both enhancer knock-outs and investigations of chromatin organisation, we show that element C possesses a dual activity: besides its classical enhancer function, it is also permanently required in cis to potentiate the autoregulatory activity of element A, by increasing its chromatin accessibility. This work uncovers a novel, asymmetrical, long-range mode of cooperation between cis-acting elements that might be essential to avoid promiscuous activation of positive autoregulatory elements.
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Hoxa2- and Rhombomere-dependent development of the mouse facial somatosensory map.
Science, 2006Co-Authors: Franck Oury, Patrick Charnay, Yasunori Murakami, Jean-sebastien Renaud, Massimo Pasqualetti, Shu-yue Ren, Filippo M RijliAbstract:In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by Rhombomere 3-derived neurons, whereas the Rhombomere 2-derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and Rhombomere 3-dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.
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Novel Activities of Mafb Underlie Its Dual Role in Hindbrain Segmentation and Regional Specification
Developmental Biology, 2003Co-Authors: François Giudicelli, Pascale Gilardi-hebenstreit, Fatima Mechta-grigoriou, Christophe Poquet, Patrick CharnayAbstract:The bZip transcription factor Mafb is expressed in two segments of the developing vertebrate hindbrain: the Rhombomeres 5 and 6. Loss of Mafb expression in the mouse mutant kreisler leads to elimination of r5 and to alterations of r6 regional identity. Here, we further investigated the role of Mafb in hindbrain patterning using gain-of-function experiments in the chick embryo. Our work has revealed novel functions for Mafb, including a positive autoregulatory activity, the capacity to repress Hoxb1 expression, and the capacity to synergise with or antagonise Krox20 activity. These different activities appear to be spatially restricted in the hindbrain, presumably due to interactions with other factors. Reinvestigation of the kreisler mutation indicated that it also results in an ectopic activation of Mafb in Rhombomere 3, accounting for the previously described molecular alterations of this Rhombomere in the mutant. Together, these data allow us to refine our view of the dual function of Mafb in both segmentation and specification of anteroposterior identity in the hindbrain.
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Hoxa1 and Krox-20 synergize to control the development of Rhombomere 3.
Development (Cambridge England), 1998Co-Authors: Françoise Helmbacher, Cristina Pujades, Carole Desmarquet, Monique Frain, François Rijli, Pierre Chambon, Patrick CharnayAbstract:The transcription factor genes Hoxa1 and Krox-20 have been shown to play important roles in vertebrate hindbrain segmentation. In this report, we present evidence for novel functions of these genes which co-operate in specifying cellular identity in Rhombomere (r) 3. Although Hoxa1 has not been observed to be expressed rostrally to the prospective r3/r4 boundary, its inactivation results in (i) the appearance of patches of cells presenting an r2-like molecular identity within r3, (ii) early neuronal differentiation in r3, normally characteristic of even-numbered Rhombomeres, and (iii) abnormal navigation of r3 motor axons, similar to that observed in even-numbered Rhombomeres. These phenotypic manifestations become more severe in the context of the additional inactivation of one allele of the Krox-20 gene, demonstrating that Hoxa1 and Krox-20 synergize in a dosage-dependent manner to specify r3 identity and odd- versus even-numbered Rhombomere characters. In addition, these data suggest that the control of the development of r3 may not be autonomous but dependent on interactions with Hoxa1-expressing cells.
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
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Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning
Development (Cambridge England), 2001Co-Authors: Olivia Wendling, Pierre Chambon, Norbert B. Ghyselinck, Manuel MarkAbstract:Mutants mice carrying targeted inactivations of both retinoic acid receptor (RAR) α and RARγ (Aα/Aγ mutants) were analyzed at different embryonic stages, in order to establish the timing of appearance of defects that we previously observed during the fetal period. We show that embryonic day (E)9.5 Aα/Aγ embryos display severe malformations, similar to those already described in retinaldehyde dehydrogenase 2 null mutants. These malformations reflect early roles of retinoic acid signaling in axial rotation, segmentation and closure of the hindbrain; formation of otocysts, pharyngeal arches and forelimb buds; and in the closure of the primitive gut. The hindbrain of E8.5 Aα/Aγ embryos shows a posterior expansion of Rhombomere 3 and 4 (R3 and R4) markers, but fails to express kreisler, a normal marker of R5 and R6. This abnormal hindbrain phenotype is strikingly different from that of embryos lacking RARα and RARβ (Aα/Aβmutants), in which we have previously shown that the territory corresponding to R5 and R6 is markedly enlarged. Administration of a pan-RAR antagonist at E8.0 to wild-type embryos cultured in vitro results in an Aα/Aβ-like hindbrain phenotype, whereas an earlier treatment at E7.0 yields an Aα/Aγ-like phenotype. Altogether, our data suggest that RARα and/or RARγ transduce the RA signal that is required first to specify the prospective R5/R6 territory, whereas RARβ is subsequently involved in setting up the caudal boundary of this territory.
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hoxa2 and hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain
Neuron, 1999Co-Authors: Marc Davenne, Pierre Chambon, Mark Maconochie, Rudiger Neun, Alexandre Pattyn, Robb Krumlauf, Filippo M RijliAbstract:Little is known about how the generation of specific neuronal types at stereotypic positions within the hindbrain is linked to Hox gene-mediated patterning. Here, we show that during neurogenesis, Hox paralog group 2 genes control both anteroposterior (A-P) and dorsoventral (D-V) patterning. Hoxa2 and Hoxb2 differentially regulate, in a Rhombomere-specific manner, the expression of several genes in broad D-V-restricted domains or narrower longitudinal columns of neuronal progenitors, immature neurons, and differentiating neuronal subtypes. Moreover, Hoxa2 and Hoxb2 can functionally synergize in controlling the development of ventral neuronal subtypes in Rhombomere 3 (r3). Thus, in addition to their roles in A-P patterning, Hoxa2 and Hoxb2 have distinct and restricted functions along the D-V axis during neurogenesis, providing insights into how neuronal fates are assigned at stereotypic positions within the hindbrain.
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Hoxa1 and Krox-20 synergize to control the development of Rhombomere 3.
Development (Cambridge England), 1998Co-Authors: Françoise Helmbacher, Cristina Pujades, Carole Desmarquet, Monique Frain, François Rijli, Pierre Chambon, Patrick CharnayAbstract:The transcription factor genes Hoxa1 and Krox-20 have been shown to play important roles in vertebrate hindbrain segmentation. In this report, we present evidence for novel functions of these genes which co-operate in specifying cellular identity in Rhombomere (r) 3. Although Hoxa1 has not been observed to be expressed rostrally to the prospective r3/r4 boundary, its inactivation results in (i) the appearance of patches of cells presenting an r2-like molecular identity within r3, (ii) early neuronal differentiation in r3, normally characteristic of even-numbered Rhombomeres, and (iii) abnormal navigation of r3 motor axons, similar to that observed in even-numbered Rhombomeres. These phenotypic manifestations become more severe in the context of the additional inactivation of one allele of the Krox-20 gene, demonstrating that Hoxa1 and Krox-20 synergize in a dosage-dependent manner to specify r3 identity and odd- versus even-numbered Rhombomere characters. In addition, these data suggest that the control of the development of r3 may not be autonomous but dependent on interactions with Hoxa1-expressing cells.
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The expression pattern of the mouse receptor tyrosine kinase gene MDK1 is conserved through evolution and requires Hoxa-2 for Rhombomere-specific expression in mouse embryos.
Developmental biology, 1996Co-Authors: Reshma Taneja, Filippo M Rijli, Bernard Thisse, Christine Thisse, Philippe Bouillet, Pascal Dollé, Pierre ChambonAbstract:Segmentation of the hindbrain has been conserved throughout the vertebrate species and results in the transient formation of Rhombomeres, which are lineage-restricted compartments. Studies on the molecular mechanisms underlying the segmentation process have revealed that rhombomeric boundaries coincide with the expression limits of several evolutionary conserved genes such as the zinc-finger transcription factor Krox-20 and homeobox genes which are expressed in a specific spatial and temporal order and have been shown to be important regulators of segmental identity. In addition to Krox-20 and Hox genes, several members of the Eph subfamily of receptor protein tyrosine kinase (RTK) genes are also expressed in a segment-restricted manner in the hindbrain, suggesting that these receptors may act in concert with Hox genes to establish regional identity. In the cascade of regulatory interactions leading to segmental identity, Krox-20 appears to act ‘‘upstream’’ of Hox genes, but the identity of the ‘‘downstream’’ effectors has not yet been identified. We report here the isolation of the zebrafish orthologue of the mouse RTK gene MDK1 which belongs to the Eph receptor subfamily and show that the major expression domains of the mouse and the zebrafish genes have been conserved through evolution. Since the coincident spatial and temporal expression of Hoxa-2 and MDK1 in the mouse hindbrain suggested a possible regulatory link between them, we analyzed the expression of the MDK1 in Hoxa-2 null mutant embryos. A selective lack of MDK1 expression in Rhombomere 3 of Hoxa-2 mutant hindbrains together with an overall altered expression pattern in the other Rhombomeres was observed, thus demonstrating that MDK1 lies downstream of Hoxa-2 in the morphogenetic signaling cascade. q 1996 Academic Press, Inc.
Pascale Gilardi-hebenstreit - One of the best experts on this subject based on the ideXlab platform.
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Krox20 hindbrain regulation incorporates multiple modes of cooperation between cis-acting elements
PLoS Genetics, 2017Co-Authors: Elodie Thierion, Patrick Charnay, Johan Le Men, Samuel Collombet, Céline Hernandez, Fanny Coulpier, Patrick Torbey, Morgane Thomas-chollier, Daan Noordermeer, Pascale Gilardi-hebenstreitAbstract:Developmental genes can harbour multiple transcriptional enhancers that act simultaneously or in succession to achieve robust and precise spatiotemporal expression. However, the mechanisms underlying cooperation between cis-acting elements are poorly documented, notably in vertebrates. The mouse gene Krox20 encodes a transcription factor required for the specification of two segments (Rhombomeres) of the developing hindbrain. In Rhombomere 3, Krox20 is subject to direct positive feedback governed by an autoregulatory enhancer, element A. In contrast, a second enhancer, element C, distant by 70 kb, is active from the initiation of transcription independent of the presence of the KROX20 protein. Here, using both enhancer knock-outs and investigations of chromatin organisation, we show that element C possesses a dual activity: besides its classical enhancer function, it is also permanently required in cis to potentiate the autoregulatory activity of element A, by increasing its chromatin accessibility. This work uncovers a novel, asymmetrical, long-range mode of cooperation between cis-acting elements that might be essential to avoid promiscuous activation of positive autoregulatory elements.
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A functional interaction between Irx and Meis patterns the anterior hindbrain and activates krox20 expression in Rhombomere 3.
Developmental biology, 2008Co-Authors: Aline Stedman, Pascale Gilardi-hebenstreit, Virginie Lecaudey, Emmanuelle Havis, Isabelle Anselme, Michel Wassef, Sylvie Schneider-maunouryAbstract:Patterning of the vertebrate hindbrain involves a segmentation process leading to the formation of seven Rhombomeres along the antero-posterior axis. While recent studies have shed light on the mechanisms underlying progressive subdivision of the posterior hindbrain into individual Rhombomeres, the early events involved in anterior hindbrain patterning are still largely unknown. In this paper we demonstrate that two zebrafish Iroquois transcription factors, Irx7 and Irx1b, are required for the proper formation and specification of Rhombomeres 1 to 4 and, in particular, for krox20 activation in r3. We also show that Irx7 functionally interacts with Meis factors to activate the expression of anterior hindbrain markers, such as hoxb1a, hoxa2 and krox20, ectopically in the anterior neural plate. Then, focusing on krox20 expression, we show that the effect of Irx7 and Meis1.1 is mediated by element C, a conserved cis-regulatory element involved in krox20 activation in the hindbrain. Together, our data point to an essential function of Iroquois transcription factors in krox20 activation and, more generally, in anterior hindbrain specification.
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Novel Activities of Mafb Underlie Its Dual Role in Hindbrain Segmentation and Regional Specification
Developmental Biology, 2003Co-Authors: François Giudicelli, Pascale Gilardi-hebenstreit, Fatima Mechta-grigoriou, Christophe Poquet, Patrick CharnayAbstract:The bZip transcription factor Mafb is expressed in two segments of the developing vertebrate hindbrain: the Rhombomeres 5 and 6. Loss of Mafb expression in the mouse mutant kreisler leads to elimination of r5 and to alterations of r6 regional identity. Here, we further investigated the role of Mafb in hindbrain patterning using gain-of-function experiments in the chick embryo. Our work has revealed novel functions for Mafb, including a positive autoregulatory activity, the capacity to repress Hoxb1 expression, and the capacity to synergise with or antagonise Krox20 activity. These different activities appear to be spatially restricted in the hindbrain, presumably due to interactions with other factors. Reinvestigation of the kreisler mutation indicated that it also results in an ectopic activation of Mafb in Rhombomere 3, accounting for the previously described molecular alterations of this Rhombomere in the mutant. Together, these data allow us to refine our view of the dual function of Mafb in both segmentation and specification of anteroposterior identity in the hindbrain.
Filippo M Rijli - One of the best experts on this subject based on the ideXlab platform.
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Hoxa2- and Rhombomere-dependent development of the mouse facial somatosensory map.
Science, 2006Co-Authors: Franck Oury, Patrick Charnay, Yasunori Murakami, Jean-sebastien Renaud, Massimo Pasqualetti, Shu-yue Ren, Filippo M RijliAbstract:In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by Rhombomere 3-derived neurons, whereas the Rhombomere 2-derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and Rhombomere 3-dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.
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hoxa2 and hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain
Neuron, 1999Co-Authors: Marc Davenne, Pierre Chambon, Mark Maconochie, Rudiger Neun, Alexandre Pattyn, Robb Krumlauf, Filippo M RijliAbstract:Little is known about how the generation of specific neuronal types at stereotypic positions within the hindbrain is linked to Hox gene-mediated patterning. Here, we show that during neurogenesis, Hox paralog group 2 genes control both anteroposterior (A-P) and dorsoventral (D-V) patterning. Hoxa2 and Hoxb2 differentially regulate, in a Rhombomere-specific manner, the expression of several genes in broad D-V-restricted domains or narrower longitudinal columns of neuronal progenitors, immature neurons, and differentiating neuronal subtypes. Moreover, Hoxa2 and Hoxb2 can functionally synergize in controlling the development of ventral neuronal subtypes in Rhombomere 3 (r3). Thus, in addition to their roles in A-P patterning, Hoxa2 and Hoxb2 have distinct and restricted functions along the D-V axis during neurogenesis, providing insights into how neuronal fates are assigned at stereotypic positions within the hindbrain.
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The expression pattern of the mouse receptor tyrosine kinase gene MDK1 is conserved through evolution and requires Hoxa-2 for Rhombomere-specific expression in mouse embryos.
Developmental biology, 1996Co-Authors: Reshma Taneja, Filippo M Rijli, Bernard Thisse, Christine Thisse, Philippe Bouillet, Pascal Dollé, Pierre ChambonAbstract:Segmentation of the hindbrain has been conserved throughout the vertebrate species and results in the transient formation of Rhombomeres, which are lineage-restricted compartments. Studies on the molecular mechanisms underlying the segmentation process have revealed that rhombomeric boundaries coincide with the expression limits of several evolutionary conserved genes such as the zinc-finger transcription factor Krox-20 and homeobox genes which are expressed in a specific spatial and temporal order and have been shown to be important regulators of segmental identity. In addition to Krox-20 and Hox genes, several members of the Eph subfamily of receptor protein tyrosine kinase (RTK) genes are also expressed in a segment-restricted manner in the hindbrain, suggesting that these receptors may act in concert with Hox genes to establish regional identity. In the cascade of regulatory interactions leading to segmental identity, Krox-20 appears to act ‘‘upstream’’ of Hox genes, but the identity of the ‘‘downstream’’ effectors has not yet been identified. We report here the isolation of the zebrafish orthologue of the mouse RTK gene MDK1 which belongs to the Eph receptor subfamily and show that the major expression domains of the mouse and the zebrafish genes have been conserved through evolution. Since the coincident spatial and temporal expression of Hoxa-2 and MDK1 in the mouse hindbrain suggested a possible regulatory link between them, we analyzed the expression of the MDK1 in Hoxa-2 null mutant embryos. A selective lack of MDK1 expression in Rhombomere 3 of Hoxa-2 mutant hindbrains together with an overall altered expression pattern in the other Rhombomeres was observed, thus demonstrating that MDK1 lies downstream of Hoxa-2 in the morphogenetic signaling cascade. q 1996 Academic Press, Inc.
Sarah Guthrie - One of the best experts on this subject based on the ideXlab platform.
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Ephrin-As play a Rhombomere-specific role in trigeminal motor axon projections in the chick embryo
Developmental biology, 2005Co-Authors: Fabrice Prin, Uma Thaker, Uwe Drescher, Sarah GuthrieAbstract:In this study, we investigate the possible role of ephrin–Eph signaling in trigeminal motor axon projections. We find that EphA receptors are expressed at higher levels by Rhombomere 2 (r2) trigeminal motor neurons than by r3 trigeminal motor neurons in the chick embryo. Mapping of Rhombomere-specific axon projections shows that r2 and r3 trigeminal motor neurons project to different muscle targets, including the mandibular adductor and the intermandibularis muscles respectively. Ephrin-A5 is expressed in these muscles, especially in some regions of the intermandibularis muscle, and can cause growth cone collapse of both r2 and r3 motor axons in vitro. We demonstrate that in vivo overexpression of ephrin-A5 in the intermandibularis muscle, or overexpression of dominant-negative EphA receptors in trigeminal motor neurons leads to a reduction in branching of r3-derived motor axons specifically. Overexpression of full-length EphA receptors impairs the formation of r3 projections to the intermandibularis muscle. These findings indicate that ephrins and their Eph receptors play a role in trigeminal motor axon topographic mapping and in Rhombomere 3-derived projections in particular.
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Rhombomere origin plays a role in the specificity of cranial motor axon projections in the chick.
The European journal of neuroscience, 1999Co-Authors: Joanne Warrilow, Sarah GuthrieAbstract:Guidance of cranial motor axons to their targets conforms to a segmental plan in the chick embryo. Trigeminal motor neurons lie within Rhombomeres 2 and 3 and project via an exit point in Rhombomere 2 to innervate the first branchial arch. Facial motor neurons lie within Rhombomeres 4 and 5 and grow out via an exit point in Rhombomere 4 to innervate the second branchial arch. We have investigated the axial level-specific matching of motor neurons and branchial arches using donor to host transplantation in avian embryos. Previous work has shown that rostrocaudal reversal of a single hindbrain segment (Rhombomere 3) leads to misprojection of a contingent of trigeminal axons via the facial nerve exit point. Using the same experimental manipulation in chick embryos and quail–chick chimaeras, we have analysed the pathways of these aberrant projections. We have found that in the majority of embryos analysed from stage 19 to 31, trigeminal axons from the transplanted Rhombomere projected towards second branchial arch muscles, in addition to their normal first arch muscle targets. However, from stage 32 to 36, aberrant projections to second arch-derived muscles were detected only in a small minority of embryos. These experiments show that trigeminal motor neurons show a lack of specificity in their early projection into the periphery but that inappropriate projections may be later eliminated. This suggests that segmental mechanisms intrinsic to the hindbrain specify motor neurons with respect to their eventual innervation pattern.