The Experts below are selected from a list of 53508 Experts worldwide ranked by ideXlab platform
Heiko Peters - One of the best experts on this subject based on the ideXlab platform.
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abstract 4471 PAX9 regulates squamous cell differentiation and alcohol associated carcinogenesis in the oro esophageal epithelium
Cancer Research, 2018Co-Authors: Zhaohui Xiong, Heiko Peters, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Katherine S Garman, Xiaoxin Luke ChenAbstract:PAX9 is a transcription factor of the Pax family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of oro-esophageal epithelium. However, its functional role in differentiation and carcinogenesis remains unclear. In this study, PAX9 deficiency in mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with an isocaloric Lieber-DeCarli liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted NMBA-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation, at least in part, contributes to alcohol-associated oro-esophageal squamous cell carcinogenesis. Citation Format: Zhaohui Xiong, Shuang Ren, Hao Chen, Yao Liu, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Ralf Kist, Heiko Peters, Katherine Garman, Zheng Sun, Xiaoxin Luke Chen. PAX9 regulates squamous cell differentiation and alcohol-associated carcinogenesis in the oro-esophageal epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4471.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro oesophageal epithelium
The Journal of Pathology, 2018Co-Authors: Ralf Kist, Zhaohui Xiong, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-esophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in the mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation may contribute to alcohol-associated oro-esophageal squamous cell carcinogenesis.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro-oesophageal epithelium.
The Journal of Pathology, 2017Co-Authors: Zhaohui Xiong, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Shuang Ren, Yao Liu, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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the formation of endoderm derived taste sensory organs requires a PAX9 dependent expansion of embryonic taste bud progenitor cells
PLOS Genetics, 2014Co-Authors: Ralf Kist, Michelle Watson, Moira Crosier, Max Robinson, Jennifer Fuchs, Julia Reichelt, Heiko PetersAbstract:In mammals, taste buds develop in different regions of the oral cavity. Small epithelial protrusions form fungiform papillae on the ectoderm-derived dorsum of the tongue and contain one or few taste buds, while taste buds in the soft palate develop without distinct papilla structures. In contrast, the endoderm-derived circumvallate and foliate papillae located at the back of the tongue contain a large number of taste buds. These taste buds cluster in deep epithelial trenches, which are generated by intercalating a period of epithelial growth between initial placode formation and conversion of epithelial cells into sensory cells. How epithelial trench formation is genetically regulated during development is largely unknown. Here we show that PAX9 acts upstream of Pax1 and Sox9 in the expanding taste progenitor field of the mouse circumvallate papilla. While a reduced number of taste buds develop in a growth-retarded circumvallate papilla of Pax1 mutant mice, its development arrests completely in PAX9-deficient mice. In addition, the PAX9 mutant circumvallate papilla trenches lack expression of K8 and Prox1 in the taste bud progenitor cells, and gradually differentiate into an epidermal-like epithelium. We also demonstrate that taste placodes of the soft palate develop through a PAX9-dependent induction. Unexpectedly, PAX9 is dispensable for patterning, morphogenesis and maintenance of taste buds that develop in ectoderm-derived fungiform papillae. Collectively, our data reveal an endoderm-specific developmental program for the formation of taste buds and their associated papilla structures. In this pathway, PAX9 is essential to generate a pool of taste bud progenitors and to maintain their competence towards prosensory cell fate induction.
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Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus.
The Journal of Pathology, 2002Co-Authors: Josef-karl Gerber, Rudi Balling, Thomas Richter, Elisabeth Kremmer, Jerzy Adamski, Heinz Höfler, Heiko PetersAbstract:Pax genes encode a family of transcription factors that play key roles in embryonic development. Whereas the functions of Pax genes in the adult organism are largely unknown, upregulated Pax gene expression has been implicated in tumourigenesis. In this study, PAX9-specific monoclonal antibodies have been generated and it has been shown that PAX9 protein is expressed in the normal epithelium of the adult human oesophagus. PAX9 expression was either lost or significantly reduced in the majority of invasive carcinomas and epithelial dysplasias, the latter representing precancerous lesions. Notably, the percentage of PAX9-positive cells within the epithelium decreased with increasing malignancy of the epithelial lesion. These results identify PAX9 as a sensitive marker for deregulated differentiation of oesophageal keratinocytes and indicate a role for PAX9 in the normal differentiation process of internal stratified squamous epithelia. These data suggest that upregulated PAX9 expression is not required for the formation of the majority of squamous cell carcinomas of the human oesophagus.
Ralf Kist - One of the best experts on this subject based on the ideXlab platform.
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abstract 4471 PAX9 regulates squamous cell differentiation and alcohol associated carcinogenesis in the oro esophageal epithelium
Cancer Research, 2018Co-Authors: Zhaohui Xiong, Heiko Peters, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Katherine S Garman, Xiaoxin Luke ChenAbstract:PAX9 is a transcription factor of the Pax family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of oro-esophageal epithelium. However, its functional role in differentiation and carcinogenesis remains unclear. In this study, PAX9 deficiency in mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with an isocaloric Lieber-DeCarli liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted NMBA-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation, at least in part, contributes to alcohol-associated oro-esophageal squamous cell carcinogenesis. Citation Format: Zhaohui Xiong, Shuang Ren, Hao Chen, Yao Liu, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Ralf Kist, Heiko Peters, Katherine Garman, Zheng Sun, Xiaoxin Luke Chen. PAX9 regulates squamous cell differentiation and alcohol-associated carcinogenesis in the oro-esophageal epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4471.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro oesophageal epithelium
The Journal of Pathology, 2018Co-Authors: Ralf Kist, Zhaohui Xiong, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-esophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in the mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation may contribute to alcohol-associated oro-esophageal squamous cell carcinogenesis.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro-oesophageal epithelium.
The Journal of Pathology, 2017Co-Authors: Zhaohui Xiong, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Shuang Ren, Yao Liu, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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the formation of endoderm derived taste sensory organs requires a PAX9 dependent expansion of embryonic taste bud progenitor cells
PLOS Genetics, 2014Co-Authors: Ralf Kist, Michelle Watson, Moira Crosier, Max Robinson, Jennifer Fuchs, Julia Reichelt, Heiko PetersAbstract:In mammals, taste buds develop in different regions of the oral cavity. Small epithelial protrusions form fungiform papillae on the ectoderm-derived dorsum of the tongue and contain one or few taste buds, while taste buds in the soft palate develop without distinct papilla structures. In contrast, the endoderm-derived circumvallate and foliate papillae located at the back of the tongue contain a large number of taste buds. These taste buds cluster in deep epithelial trenches, which are generated by intercalating a period of epithelial growth between initial placode formation and conversion of epithelial cells into sensory cells. How epithelial trench formation is genetically regulated during development is largely unknown. Here we show that PAX9 acts upstream of Pax1 and Sox9 in the expanding taste progenitor field of the mouse circumvallate papilla. While a reduced number of taste buds develop in a growth-retarded circumvallate papilla of Pax1 mutant mice, its development arrests completely in PAX9-deficient mice. In addition, the PAX9 mutant circumvallate papilla trenches lack expression of K8 and Prox1 in the taste bud progenitor cells, and gradually differentiate into an epidermal-like epithelium. We also demonstrate that taste placodes of the soft palate develop through a PAX9-dependent induction. Unexpectedly, PAX9 is dispensable for patterning, morphogenesis and maintenance of taste buds that develop in ectoderm-derived fungiform papillae. Collectively, our data reveal an endoderm-specific developmental program for the formation of taste buds and their associated papilla structures. In this pathway, PAX9 is essential to generate a pool of taste bud progenitors and to maintain their competence towards prosensory cell fate induction.
Zhaohui Xiong - One of the best experts on this subject based on the ideXlab platform.
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abstract 4471 PAX9 regulates squamous cell differentiation and alcohol associated carcinogenesis in the oro esophageal epithelium
Cancer Research, 2018Co-Authors: Zhaohui Xiong, Heiko Peters, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Katherine S Garman, Xiaoxin Luke ChenAbstract:PAX9 is a transcription factor of the Pax family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of oro-esophageal epithelium. However, its functional role in differentiation and carcinogenesis remains unclear. In this study, PAX9 deficiency in mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with an isocaloric Lieber-DeCarli liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted NMBA-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation, at least in part, contributes to alcohol-associated oro-esophageal squamous cell carcinogenesis. Citation Format: Zhaohui Xiong, Shuang Ren, Hao Chen, Yao Liu, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Ralf Kist, Heiko Peters, Katherine Garman, Zheng Sun, Xiaoxin Luke Chen. PAX9 regulates squamous cell differentiation and alcohol-associated carcinogenesis in the oro-esophageal epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4471.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro oesophageal epithelium
The Journal of Pathology, 2018Co-Authors: Ralf Kist, Zhaohui Xiong, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-esophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in the mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated PAX9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 down-regulation may contribute to alcohol-associated oro-esophageal squamous cell carcinogenesis.
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PAX9 regulates squamous cell differentiation and carcinogenesis in the oro-oesophageal epithelium.
The Journal of Pathology, 2017Co-Authors: Zhaohui Xiong, Ralf Kist, Hao Chen, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Shuang Ren, Yao Liu, Heiko PetersAbstract:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, PAX9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or PAX9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Meinrad Busslinger - One of the best experts on this subject based on the ideXlab platform.
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pax2 8 regulated gata3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney
Development, 2006Co-Authors: David Grote, Abdallah Souabni, Meinrad Busslinger, Maxime BouchardAbstract:The mammalian pro- and mesonephros are transient embryonic kidneys essential for urogenital system development. The nephric (Wolffian) duct, which is a central constituent of both structures, elongates caudally along a stereotypical path to reach the hindlimb level where it induces metanephros (adult kidney) formation, while the remaining duct gives rise to the male genital tract (epidydimis, vas deferens). The transcription factors Pax2 and Pax8 are essential for the initiation of pro- and mesonephros development. In a cDNA microarray screen for genes specifically expressed in the pro/mesonephros and regulated by Pax proteins, we identified Gata3, a transcription factor gene associated with hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. Gata3 is already expressed in the pronephric anlage, together with Pax2 and Pax8, suggesting that it may be a direct Pax2/8 target gene. Inactivation of Gata3 by insertion of an Ires-GFP reporter gene resulted in a massive increase in nephric duct cellularity, which was accompanied by enhanced cell proliferation and aberrant elongation of the nephric duct. Interestingly, however, the nephrogenic cord extended, with delayed kinetics, along the entire caudal path up to the level of the hindlimb bud, indicating that extension of the nephric duct and cord is controlled by different guidance cues. At the molecular level, the nephric duct of Gata3-/- embryos is characterized by the loss of Ret expression and signaling, which may contribute to the guidance defect of the nephric duct. Together, these results define Gata3 as a key regulator of nephric duct morphogenesis and guidance in the pro/mesonephric kidney.
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nephric lineage specification by pax2 and pax8
Genes & Development, 2002Co-Authors: Maxime Bouchard, Abdallah Souabni, Markus Mandler, Annette Neubuser, Meinrad BusslingerAbstract:The mammalian kidney develops in three successive steps from the initial pronephros via the mesonephros to the adult metanephros. Although the nephric lineage is specified during pronephros induction, no single regulator, including the transcription factor Pax2 or Pax8, has yet been identified to control this initial phase of kidney development. In this paper, we demonstrate that mouse embryos lacking both Pax2 and Pax8 are unable to form the pronephros or any later nephric structures. In these double-mutant embryos, the intermediate mesoderm does not undergo the mesenchymal-epithelial transitions required for nephric duct formation, fails to initiate the kidney-specific expression of Lim1 and c-Ret, and is lost by apoptosis 1 d after failed pronephric induction. Conversely, retroviral misexpression of Pax2 was sufficient to induce ectopic nephric structures in the intermediate mesoderm and genital ridge of chick embryos. Together, these data identify Pax2 and Pax8 as critical regulators that specify the nephric lineage.
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functional equivalence of the transcription factors pax2 and pax5 in mouse development
Development, 2000Co-Authors: Maxime Bouchard, Peter Pfeffer, Meinrad BusslingerAbstract:Pax2 and Pax5 arose by gene duplication at the onset of vertebrate evolution and have since diverged in their developmental expression patterns. They are expressed in different organs of the mouse embryo except for their coexpression at the midbrain-hindbrain boundary (MHB), which functions as an organizing center to control midbrain and cerebellum development. During MHB development, Pax2 expression is initiated prior to Pax5 transcription, and Pax2(−/−) embryos fail to generate the posterior midbrain and cerebellum, whereas Pax5(−/−) mice exhibit only minor patterning defects in the same brain regions. To investigate whether these contrasting phenotypes are caused by differences in the temporal expression or biochemical activity of these two transcription factors, we have generated a knock-in (ki) mouse, which expresses a Pax5 minigene under the control of the Pax2 locus. Midbrain and cerebellum development was entirely rescued in Pax2(5ki/5ki) embryos. Pax5 could furthermore completely substitute for the Pax2 function during morphogenesis of the inner ear and genital tracts, despite the fact that the Pax5 transcript of the Pax2(5ki)allele was expressed only at a fivefold lower level than the wild-type Pax2 mRNA. As a consequence, the Pax2(5ki)allele was able to rescue most but not all Pax2 mutant defects in the developing eye and kidney, both of which are known to be highly sensitive to Pax2 protein dosage. Together these data demonstrate that the transcription factors Pax2 and Pax5 have maintained equivalent biochemical functions since their divergence early in vertebrate evolution.
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pax2 5 and pax6 subdivide the early neural tube into three domains
Mechanisms of Development, 1999Co-Authors: Martin K. Schwarz, Gonzalo Alvarezbolado, Gregory R. Dressler, Meinrad Busslinger, Pavel Urbánek, Peter GrussAbstract:The nested expression patterns of the paired-box containing transcription factors Pax2/5 and Pax6 demarcate the midbrain and forebrain primordium at the neural plate stage. We demonstrate that, in Pax2/5 deficient mice, the mesencephalon/metencephalon primordium is completely missing, resulting in a fusion of the forebrain to the hindbrain. Morphologically, in the alar plate the deletion is characterized by the substitution of the tectum (dorsal midbrain) and cerebellum (dorsal metencephalon) by the caudal diencephalon and in the basal plate by the replacement of the midbrain tegmentum by the ventral metencephalon (pons). Molecularly, the loss of the tectum is demonstrated by an expanded expression of Pax6, (the molecular determinant of posterior commissure), and a rostral shift of the territory of expression of Gbx2 and Otp (markers for the pons), towards the caudal diencephalon. Our results suggest that an intact territory of expression of Pax2/5 in the neural plate, nested between the rostral and caudal territories of expression of Pax6, is necessary for defining the midbrain vesicle.
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characterization of three novel members of the zebrafish pax2 5 8 family dependency of pax5 and pax8 expression on the pax2 1 noi function
Development, 1998Co-Authors: Peter Pfeffer, Thomas Gerster, Michael Brand, Meinrad BusslingerAbstract:The mammalian Pax2, Pax5 and Pax8 genes code for highly related transcription factors, which play important roles in embryonic development and organogenesis. Here we report the characterization of all members of the zebrafish Pax2/5/8 family. These genes have arisen by duplications before or at the onset of vertebrate evolution. Due to an additional genome amplification in the fish lineage, the zebrafish contains two Pax2 genes, the previously known Pax[b] gene (here renamed as Pax2.1) and a novel Pax2.2 gene. The zebrafish Pax2.1 gene most closely resembles the mammalian Pax2 gene in its expression pattern, as it is transcribed first in the midbrain-hindbrain boundary region, then in the optic stalk, otic system, pronephros and nephric ducts, and lastly in specific interneurons of the hindbrain and spinal cord. Pax2.2 differs from Pax2.1 by the absence of expression in the nephric system and by a delayed onset of transcription in other Pax2.1 expession domains. Pax8 is also expressed in the same domains as Pax2.1, but its transcription is already initiated during gastrulation in the primordia of the otic placode and pronephric anlage, thus identifying Pax8 as the earliest developmental marker of these structures. The zebrafish Pax5 gene, in contrast to its mouse orthologue, is transcribed in the otic system in addition to its prominent expression at the midbrain-hindbrain boundary. The no isthmus (noi) mutation is known to inactivate the Pax2.1 gene, thereby affecting the development of the midbrain-hindbrain boundary region, pronephric system, optic stalk and otic region. Although the different members of the Pax2/5/8 family may potentially compensate for the loss of Pax2.1 function, we demonstrate here that only the expression of the Pax2.2 gene remains unaffected in noi mutant embryos. The expression of Pax5 and Pax8 is either not initiated at the midbrain-hindbrain boundary or is later not maintained in other expression domains. Consequently, the noi mutation of zebrafish is equivalent to combined inactivation of the mouse Pax2 and Pax5 genes with regard to the loss of midbrain-hindbrain boundary development.
Rudi Balling - One of the best experts on this subject based on the ideXlab platform.
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Pax1 and PAX9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome.
Development, 2003Co-Authors: Isabel Rodrigo, Rudi Balling, Robert E. Hill, Andrea Münsterberg, Kenji ImaiAbstract:We have previously shown that the paired-box transcription factors Pax1 and PAX9 synergistically act in the proper formation of the vertebral column. Nevertheless, downstream events of the Pax1/PAX9 action and their target genes remain to be elucidated. We show, by analyzing Pax1;PAX9 double mutant mice, that expression of Bapx1 in the sclerotome requires the presence of Pax1 and PAX9, in a gene dose-dependent manner. By using a retroviral system to overexpress Pax1 in chick presomitic mesoderm explants, we show that Pax1 can substitute for Shh in inducing Bapx1 expression and in initiating chondrogenic differentiation. Furthermore, we demonstrate that Pax1 and PAX9 can transactivate regulatory sequences in the Bapx1 promoter and that they physically interact with the Bapx1 promoter region. These results strongly suggest that Bapx1 is a direct target of Pax1 and PAX9. Together, we conclude that Pax1 and PAX9 are required and sufficient for the chondrogenic differentiation of sclerotomal cells.
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Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus.
The Journal of Pathology, 2002Co-Authors: Josef-karl Gerber, Rudi Balling, Thomas Richter, Elisabeth Kremmer, Jerzy Adamski, Heinz Höfler, Heiko PetersAbstract:Pax genes encode a family of transcription factors that play key roles in embryonic development. Whereas the functions of Pax genes in the adult organism are largely unknown, upregulated Pax gene expression has been implicated in tumourigenesis. In this study, PAX9-specific monoclonal antibodies have been generated and it has been shown that PAX9 protein is expressed in the normal epithelium of the adult human oesophagus. PAX9 expression was either lost or significantly reduced in the majority of invasive carcinomas and epithelial dysplasias, the latter representing precancerous lesions. Notably, the percentage of PAX9-positive cells within the epithelium decreased with increasing malignancy of the epithelial lesion. These results identify PAX9 as a sensitive marker for deregulated differentiation of oesophageal keratinocytes and indicate a role for PAX9 in the normal differentiation process of internal stratified squamous epithelia. These data suggest that upregulated PAX9 expression is not required for the formation of the majority of squamous cell carcinomas of the human oesophagus.
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pax1 and PAX9 synergistically regulate vertebral column development
Development, 1999Co-Authors: Heiko Peters, Bettina Wilm, Norio Sakai, Kenji Imai, Richard L Maas, Rudi BallingAbstract:The paralogous genes Pax1 and PAX9 constitute one group within the vertebrate Pax gene family. They encode closely related transcription factors and are expressed in similar patterns during mouse embryogenesis, suggesting that Pax1 and PAX9 act in similar developmental pathways. We have recently shown that mice homozygous for a defined Pax1 null allele exhibit morphological abnormalities of the axial skeleton, which is not affected in homozygous PAX9 mutants. To investigate a potential interaction of the two genes, we analysed Pax1/PAX9 double mutant mice. These mutants completely lack the medial derivatives of the sclerotomes, the vertebral bodies, intervertebral discs and the proximal parts of the ribs. This phenotype is much more severe than that of Pax1 single homozygous mutants. In contrast, the neural arches, which are derived from the lateral regions of the sclerotomes, are formed. The analysis of PAX9 expression in compound mutants indicates that both spatial expansion and upregulation of PAX9 expression account for its compensatory function during sclerotome development in the absence of Pax1. In Pax1/PAX9 double homozygous mutants, formation and anteroposterior polarity of sclerotomes, as well as induction of a chondrocyte-specific cell lineage, appear normal. However, instead of a segmental arrangement of vertebrae and intervertebral disc anlagen, a loose mesenchyme surrounding the notochord is formed. The gradual loss of Sox9 and Collagen II expression in this mesenchyme indicates that the sclerotomes are prevented from undergoing chondrogenesis. The first detectable defect is a low rate of cell proliferation in the ventromedial regions of the sclerotomes after sclerotome formation but before mesenchymal condensation normally occurs. At later stages, an increased number of cells undergoing apoptosis further reduces the area normally forming vertebrae and intervertebral discs. Our results reveal functional redundancy between Pax1 and PAX9 during vertebral column development and identify an early role of Pax1 and PAX9 in the control of cell proliferation during early sclerotome development. In addition, our data indicate that the development of medial and lateral elements of vertebrae is regulated by distinct genetic pathways.
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PAX9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities
Genes & Development, 1998Co-Authors: Heiko Peters, Annette Neubuser, Klaus Kratochwil, Rudi BallingAbstract:Pax genes have been shown to play important roles in mammalian development and organogenesis. PAX9, a member of this transcription factor family, is expressed in somites, pharyngeal pouches, mesenchyme involved in craniofacial, tooth, and limb development, as well as other sites during mouse embryogenesis. To analyze its function in vivo, we generated PAX9 deficient mice and show that PAX9 is essential for the development of a variety of organs and skeletal elements. Homozygous PAX9-mutant mice die shortly after birth, most likely as a consequence of a cleft secondary palate. They lack a thymus, parathyroid glands, and ultimobranchial bodies, organs which are derived from the pharyngeal pouches. In all limbs, a supernumerary preaxial digit is formed, but the flexor of the hindlimb toes is missing. Furthermore, craniofacial and visceral skeletogenesis is disturbed, and all teeth are absent. In PAX9-deficient embryos tooth development is arrested at the bud stage. At this stage, PAX9 is required for the mesenchymal expression of Bmp4, Msx1, and Lef1, suggesting a role for PAX9 in the establishment of the inductive capacity of the tooth mesenchyme. In summary, our analysis shows that PAX9 is a key regulator during the development of a wide range of organ primordia.
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Pax genes and organogenesis: PAX9 meets tooth development
European Journal of Oral Sciences, 1998Co-Authors: Heiko Peters, Annette Neubuser, Rudi BallingAbstract:Pax genes encode a family of transcription factors that play key roles during embryogenesis. They are required for the development of a variety of organs including the nervous and muscular system, skeleton, eye, ear, kidney, thymus, and pancreas. Whereas the developmental roles of many of the nine known Pax genes have been analyzed in great detail, a functional analysis of PAX9 has just begun. During mouse embryogenesis, PAX9 exhibits a highly specific expression pattern in derivatives of the foregut endoderm, somites, limb mesenchyme, midbrain, and the cephalic neural crest. In the mandibular arch mesenchyme, the expression of PAX9 marks the prospective sites of tooth development prior to any morphological signs of odontogenesis and is maintained in the developing tooth mesenchyme thereafter. To understand the function of PAX9 during mouse embryogenesis, we recently have created a null allele by gene targeting. Preliminary analyses show that PAX9 is essential for the formation of teeth, and we conclude that PAX9 is required for tooth development to proceed beyond the bud stage. Here, we briefly summarize our current knowledge about Pax genes and introduce PAX9 to the growing family of factors which are involved in tooth development.
