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Guillermo Oliver - One of the best experts on this subject based on the ideXlab platform.
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SIX3 dosage mediates the pathogenesis of holoprosencephaly
Development, 2016Co-Authors: Xin Geng, Oleg Lagutin, Sandra Acosta, Guillermo OliverAbstract:Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic SIX3 allele, we demonstrate in mice that variability in SIX3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in SIX3 dosage result in different forms of HPE.
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SIX3 is required for ependymal cell maturation
Development, 2011Co-Authors: Alfonso Lavado, Guillermo OliverAbstract:Ependymal cells are part of the neurogenic niche in the adult subventricular zone of the lateral ventricles, where they regulate neurogenesis and neuroblast migration. Ependymal cells are generated from radial glia cells during embryonic brain development and acquire their final characteristics postnatally. The homeobox gene SIX3 is expressed in ependymal cells during the formation of the lateral wall of the lateral ventricles in the brain. Here, we show that SIX3 is necessary for ependymal cell maturation during postnatal stages of brain development. In its absence, ependymal cells fail to suppress radial glia characteristics, resulting in a defective lateral wall, abnormal neuroblast migration and differentiation, and hydrocephaly.
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neuroretina specification in mouse embryos requires SIX3 mediated suppression of wnt8b in the anterior neural plate
Journal of Clinical Investigation, 2010Co-Authors: Oleg Lagutin, Eric C Swindell, Milan Jamrich, Guillermo OliverAbstract:Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell–based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis–related homeobox 3 (SIX3) as a crucial player in this process in mice. In SIX3 conditional–mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of SIX3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to SIX3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified SIX3-responsive elements in the Wnt8b locus and demonstrated that SIX3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.
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regulation of a remote shh forebrain enhancer by the SIX3 homeoprotein
Nature Genetics, 2008Co-Authors: Yongsu Jeong, Federico Coluccio Leskow, Kenia B Eljaick, Erich Roessler, Maximilian Muenke, Anastasia Yocum, Christele Dubourg, Xue Li, Xin Geng, Guillermo OliverAbstract:In humans, SHH haploinsufficiency results in holoprosencephaly (HPE), a defect in anterior midline formation. Despite the importance of maintaining SHH transcript levels above a critical threshold, we know little about the upstream regulators of SHH expression in the forebrain. Here we describe a rare nucleotide variant located 460 kb upstream of SHH in an individual with HPE that resulted in the loss of Shh brain enhancer-2 (SBE2) activity in the hypothalamus of transgenic mouse embryos. Using a DNA affinity-capture assay, we screened the SBE2 sequence for DNA-binding proteins and identified members of the SIX3 and Six6 homeodomain family as candidate regulators of Shh transcription. SIX3 showed reduced binding affinity for the mutant compared to the wild-type SBE2 sequence. Moreover, SIX3 with HPE-causing alterations failed to bind and activate SBE2. These data suggest a direct link between SIX3 and Shh regulation during normal forebrain development and in the pathogenesis of HPE.
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haploinsufficiency of SIX3 fails to activate sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly
Developmental Cell, 2008Co-Authors: Xin Geng, Yongsu Jeong, Lilianna Solnicakrezel, Adi Inbal, Oleg Lagutin, Christina K Speirs, Douglas J Epstein, Guillermo OliverAbstract:Holoprosencephaly (HPE), the most common forebrain malformation, is characterized by an incomplete separation of the cerebral hemispheres. Mutations in the homeobox gene SIX3 account for 1.3% of all cases of human HPE. Using zebrafish-based assays, we have now determined that HPE-associated SIX3 mutant proteins function as hypomorphs. Haploinsufficiency of SIX3 caused by deletion of one allele of SIX3 or by replacement of wild-type SIX3 with HPE-associated SIX3 mutant alleles was sufficient to recapitulate in mouse models most of the phenotypic features of human HPE. We demonstrate that Shh is a direct target of SIX3 in the rostral diencephalon ventral midline (RDVM). Reduced amounts of functional SIX3 protein fail to activate Shh expression in the mutant RDVM and ultimately lead to HPE. These results identify SIX3 as a direct regulator of Shh expression and reveal a crossregulatory loop between Shh and SIX3 in the ventral forebrain.
Zhibin Yu - One of the best experts on this subject based on the ideXlab platform.
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the egfr znf263 signaling axis silences SIX3 in glioblastoma epigenetically
Oncogene, 2020Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Jianbo Feng, Wei Wang, Lan Xiao, Minghua WuAbstract:The homeotic protein SIX3 is a transcription factor vital for neurogenesis and has a bivalent promoter. We previously showed that SIX3 can be transcriptionally silenced by DNA hypermethylation, functions as a tumor suppressor gene, and inhibits human glioblastoma transcriptionally. Here, we show that the activation of epidermal growth factor (EGFR) induces DNA methylation of SIX3 promoter through the MAPK pathway. ERK, when activated, binds with ZNF263, consequently abrogating the ubiquitination of ZNF263 and leading to its stabilization. ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and methylation of SIX3 promoter. Activation of the EGFR-ZNF263 signaling axis in phenotypically normal astrocytes or glioblastoma cells triggers or enhances tumorigenic activities, while elevated expression of the EGFR-ZNF263 signaling components in glioblastoma tissues is associated with poor prognosis of the patients. Together, our findings demonstrate that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma.
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SIX3 a tumor suppressor inhibits astrocytoma tumorigenesis by transcriptional repression of aurka b
Journal of Hematology & Oncology, 2017Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Chunhua Zhao, Peiyao LiAbstract:SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
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SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
Journal of Hematology & Oncology, 2017Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Chunhua ZhaoAbstract:SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
Peiyao Li - One of the best experts on this subject based on the ideXlab platform.
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SIX3 a tumor suppressor inhibits astrocytoma tumorigenesis by transcriptional repression of aurka b
Journal of Hematology & Oncology, 2017Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Chunhua Zhao, Peiyao LiAbstract:SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
Yan Zhang - One of the best experts on this subject based on the ideXlab platform.
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the egfr znf263 signaling axis silences SIX3 in glioblastoma epigenetically
Oncogene, 2020Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Jianbo Feng, Wei Wang, Lan Xiao, Minghua WuAbstract:The homeotic protein SIX3 is a transcription factor vital for neurogenesis and has a bivalent promoter. We previously showed that SIX3 can be transcriptionally silenced by DNA hypermethylation, functions as a tumor suppressor gene, and inhibits human glioblastoma transcriptionally. Here, we show that the activation of epidermal growth factor (EGFR) induces DNA methylation of SIX3 promoter through the MAPK pathway. ERK, when activated, binds with ZNF263, consequently abrogating the ubiquitination of ZNF263 and leading to its stabilization. ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and methylation of SIX3 promoter. Activation of the EGFR-ZNF263 signaling axis in phenotypically normal astrocytes or glioblastoma cells triggers or enhances tumorigenic activities, while elevated expression of the EGFR-ZNF263 signaling components in glioblastoma tissues is associated with poor prognosis of the patients. Together, our findings demonstrate that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma.
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SIX3 a tumor suppressor inhibits astrocytoma tumorigenesis by transcriptional repression of aurka b
Journal of Hematology & Oncology, 2017Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Chunhua Zhao, Peiyao LiAbstract:SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
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SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
Journal of Hematology & Oncology, 2017Co-Authors: Zhibin Yu, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Chunhua ZhaoAbstract:SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
Peter Gruss - One of the best experts on this subject based on the ideXlab platform.
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mutually regulated expression of pax6 and SIX3 and its implications for the pax6 haploinsufficient lens phenotype
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Guy Goudreau, Jochen Graw, Petros Petrou, Lixing W Reneker, Jana Loster, Peter GrussAbstract:Pax6 is a key regulator of eye development in vertebrates and invertebrates, and heterozygous loss-of-function mutations of the mouse Pax6 gene result in the Small eye phenotype, in which a small lens is a constant feature. To provide an understanding of the mechanisms underlying this haploinsufficient phenotype, we evaluated in Pax6 heterozygous mice the effects of reduced Pax6 gene dosage on the activity of other transcription factors regulating eye formation. We found that SIX3 expression was specifically reduced in lenses of Pax6 heterozygous mouse embryos. Interactions between orthologous genes from the Pax and Six families have been identified in Drosophila and vertebrate species, and we examined the control of Pax6 and SIX3 gene expression in the developing mouse lens. Using in vitro and transgenic approaches, we found that either transcription factor binds regulatory sequences from the counterpart gene and that both genes mutually activate their expression. These studies define a functional relationship in the lens in which SIX3 expression is dosage-dependent on Pax6 and where, conversely, SIX3 activates Pax6. Accordingly, we show a rescue of the Pax6 haploinsufficient lens phenotype after lens-specific expression of SIX3 in transgenic mice. This phenotypic rescue was accompanied by cell proliferation and activation of the platelet-derived growth factor α-R/cyclin D1 signaling pathway. Our findings thus provide a mechanism implicating gene regulatory interactions between Pax6 and SIX3 in the tissue-specific defects found in Pax6 heterozygous mice.
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cloning and expression of xSIX3 the xenopus homologue of murine SIX3
Mechanisms of Development, 2000Co-Authors: Xunlei Zhou, Thomas Hollemann, Tomas Pieler, Peter GrussAbstract:Abstract The vertebrate Six family of transcription factor genes are homologues of the fruitfly gene sine oculis (so). Human, murine, avian and fish (medaka, zebrafish) homologues have recently been cloned. We report the cloning and developmental pattern of expression of xSIX3, the Xenopus laevis homologue of SIX3. In addition, we have compared all the known sequences of vertebrate SIX3 genes. xSIX3 is very homologous to SIX3 in other vertebrates in terms of amino acid sequence. The reported developmental pattern of expression of SIX3 in chick and mouse includes not only the developing eyes and the ventral diencephalic tissue between them, but also a large, sagittally-oriented telencephalic region. The distribution of xSIX3, however, is virtually restricted to the eyes and ventral diencephalon, showing only a very small territory of expression in the telencephalon.
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gene expression pattern cloning and expression of xSIX3 the xenopus homologue of murine SIX3
2000Co-Authors: Xunlei Zhou, Thomas Hollemann, Tomas Pieler, Peter GrussAbstract:The vertebrate Six family of transcription factor genes are homologues of the fruitfly gene sine oculis (so). Human, murine, avian and fish (medaka, zebrafish) homologues have recently been cloned. We report the cloning and developmental pattern of expression of xSIX3, the Xenopus laevis homologue of SIX3. In addition, we have compared all the known sequences of vertebrate SIX3 genes. xSIX3 is very homologous to SIX3 in other vertebrates in terms of amino acid sequence. The reported developmental pattern of expression of SIX3 in chick and mouse includes not only the developing eyes and the ventral diencephalic tissue between them, but also a large, sagittally-oriented telencephalic region. The distribution of xSIX3, however, is virtually restricted to the eyes and ventral diencephalon, showing only a very small territory of expression in the telencephalon. q 2000 Elsevier Science Ireland Ltd. All rights reserved.
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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.
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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.
