The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Sophia Y. Tsai - One of the best experts on this subject based on the ideXlab platform.
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nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical fancd2 pathway
Science Advances, 2019Co-Authors: Jun Qin, Ming-jer Tsai, Leiming Wang, Huiju Lee, Chungyang Kao, Dan Liu, Zhou Songyang, Junjie Chen, Sophia Y. TsaiAbstract:Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.
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elimination of the male reproductive tract in the female embryo is promoted by coup tfii in mice
Yearbook of Paediatric Endocrinology, 2018Co-Authors: Fei Zhao, Sophia Y. Tsai, Ming-jer Tsai, Heather L Franco, Karina F Rodriguez, Paula R Brown, Humphrey H C YaoAbstract:The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default because the male reproductive tracts (Wolffian ducts) in the female degenerate owing to a lack of androgen. Here, we discovered that female mouse embryos lacking COUP-TFII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex—possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. We thus suggest that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance.
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the role of coup tfii in striated muscle development and disease
Current Topics in Developmental Biology, 2017Co-Authors: Sanpin Wu, Ming-jer Tsai, Sophia Y. TsaiAbstract:Skeletal and cardiac muscles are the only striated muscles in the body. Although sharing many structural and functional similarities, skeletal and cardiac muscles have intrinsic differences in terms of physiology and regenerative potential. While skeletal muscle possesses a robust regenerative response, the mammalian heart has limited repair capacity after birth. In this review, we provide an updated view regarding chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) function in vertebrate myogenesis, with particular emphasis on the skeletal and cardiac muscles. We also highlight the new insights of COUP-TFII hyperactivity underlying striated muscle dysfunction. Lastly, we discuss the challenges and strategies in translating COUP-TFII action for clinical intervention.
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Endocardial Cushion Morphogenesis and Coronary Vessel Development Require Chicken Ovalbumin Upstream Promoter-Transcription Factor II
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Fu-jung Lin, Ming-jer Tsai, Li-ru You, Wen-hsin Hsu, Sophia Y. TsaiAbstract:Objective— Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis. Methods and Results— We analyzed embryos deficient in COUP-TFII and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific COUP-TFII mutants and molecular approaches, we show that COUP-TFII deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of Snai1 , one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation. Conclusion— Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.
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generation of es cells for conditional expression of nuclear receptors and coregulators in vivo
Molecular Endocrinology, 2010Co-Authors: Dongkee Lee, Sophia Y. Tsai, Francesco J Demayo, Ming-jer TsaiAbstract:Nuclear receptors and coregulators orchestrate diverse aspects of biological functions and inappropriate expression of these factors often associates with human diseases. The present study describes a conditional overexpression system consisting of a minigene located at the Rosa26 locus in the genome of mouse embryonic stem (ES) cells. Before activation, the minigene is silent due to a floxed STOP cassette inserted between the promoter and the transgene. Upon cre-mediated excision of the STOP cassette, the minigene constitutively expresses the tagged transgene driven by the ubiquitous CAGGS promoter. Thus, this system can be used to express target gene in any tissue in a spatial and/or temporal manner if respective cre mouse lines are available. Serving as proof of principle, the CAG-S-hCOUP-TFI allele was generated in ES cells and subsequently in mice. This allele was capable of conditionally overexpressing human chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) in all tissues tested upon activation by cre drivers. This allele was further subjected to address functionality of expressed COUP-TFI and the functional similarity between COUP-TFI and COUP-TFII. Expression of COUP-TFI in COUP-TFII-ablated uterus suppressed aberrant estrogen receptor-α activities and rescued implantation and decidualization defects of COUP-TFII mutants, suggesting that COUP-TFI and COUP-TFII are able to functionally compensate for each other in the uterus. A toolbox currently under construction will contain ES cell lines for overexpressing all 48 nuclear receptors and selected 10 coregulators. Upon completion, it will be a very valuable resource for the scientific community. Several ES cells are currently available for distribution.
Ming-jer Tsai - One of the best experts on this subject based on the ideXlab platform.
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nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical fancd2 pathway
Science Advances, 2019Co-Authors: Jun Qin, Ming-jer Tsai, Leiming Wang, Huiju Lee, Chungyang Kao, Dan Liu, Zhou Songyang, Junjie Chen, Sophia Y. TsaiAbstract:Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.
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elimination of the male reproductive tract in the female embryo is promoted by coup tfii in mice
Yearbook of Paediatric Endocrinology, 2018Co-Authors: Fei Zhao, Sophia Y. Tsai, Ming-jer Tsai, Heather L Franco, Karina F Rodriguez, Paula R Brown, Humphrey H C YaoAbstract:The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default because the male reproductive tracts (Wolffian ducts) in the female degenerate owing to a lack of androgen. Here, we discovered that female mouse embryos lacking COUP-TFII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex—possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. We thus suggest that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance.
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the role of coup tfii in striated muscle development and disease
Current Topics in Developmental Biology, 2017Co-Authors: Sanpin Wu, Ming-jer Tsai, Sophia Y. TsaiAbstract:Skeletal and cardiac muscles are the only striated muscles in the body. Although sharing many structural and functional similarities, skeletal and cardiac muscles have intrinsic differences in terms of physiology and regenerative potential. While skeletal muscle possesses a robust regenerative response, the mammalian heart has limited repair capacity after birth. In this review, we provide an updated view regarding chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) function in vertebrate myogenesis, with particular emphasis on the skeletal and cardiac muscles. We also highlight the new insights of COUP-TFII hyperactivity underlying striated muscle dysfunction. Lastly, we discuss the challenges and strategies in translating COUP-TFII action for clinical intervention.
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Endocardial Cushion Morphogenesis and Coronary Vessel Development Require Chicken Ovalbumin Upstream Promoter-Transcription Factor II
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Fu-jung Lin, Ming-jer Tsai, Li-ru You, Wen-hsin Hsu, Sophia Y. TsaiAbstract:Objective— Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis. Methods and Results— We analyzed embryos deficient in COUP-TFII and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific COUP-TFII mutants and molecular approaches, we show that COUP-TFII deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of Snai1 , one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation. Conclusion— Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.
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generation of es cells for conditional expression of nuclear receptors and coregulators in vivo
Molecular Endocrinology, 2010Co-Authors: Dongkee Lee, Sophia Y. Tsai, Francesco J Demayo, Ming-jer TsaiAbstract:Nuclear receptors and coregulators orchestrate diverse aspects of biological functions and inappropriate expression of these factors often associates with human diseases. The present study describes a conditional overexpression system consisting of a minigene located at the Rosa26 locus in the genome of mouse embryonic stem (ES) cells. Before activation, the minigene is silent due to a floxed STOP cassette inserted between the promoter and the transgene. Upon cre-mediated excision of the STOP cassette, the minigene constitutively expresses the tagged transgene driven by the ubiquitous CAGGS promoter. Thus, this system can be used to express target gene in any tissue in a spatial and/or temporal manner if respective cre mouse lines are available. Serving as proof of principle, the CAG-S-hCOUP-TFI allele was generated in ES cells and subsequently in mice. This allele was capable of conditionally overexpressing human chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) in all tissues tested upon activation by cre drivers. This allele was further subjected to address functionality of expressed COUP-TFI and the functional similarity between COUP-TFI and COUP-TFII. Expression of COUP-TFI in COUP-TFII-ablated uterus suppressed aberrant estrogen receptor-α activities and rescued implantation and decidualization defects of COUP-TFII mutants, suggesting that COUP-TFI and COUP-TFII are able to functionally compensate for each other in the uterus. A toolbox currently under construction will contain ES cell lines for overexpressing all 48 nuclear receptors and selected 10 coregulators. Upon completion, it will be a very valuable resource for the scientific community. Several ES cells are currently available for distribution.
Li-ru You - One of the best experts on this subject based on the ideXlab platform.
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COUP-TFII is required for morphogenesis of the neural crest-derived tympanic ring
Nature Publishing Group, 2017Co-Authors: Wen-hsin Hsu, Chun-ming Chen, Li-ru YouAbstract:Abstract Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) plays pivotal roles in cell growth, cell differentiation, and cell fate determination. Although genome-wide studies have identified COUP-TFII binding on gene sets mainly involved in neural crest cell (NCC) development and craniofacial morphogenesis, the direct functional connection between COUP-TFII and NCCs in vivo has not been well characterized. In this study, we show that COUP-TFII is expressed in the subpopulation of NCCs and its derivatives, and targeted ablation of COUP-TFII in mouse NCCs results in markedly shortened and bifurcated tympanic rings, which in turn disturb the caudal direction of external acoustic meatus invagination. However, formation of the manubrium of the malleus (MM) in Wnt1-Cre/+;COUP-TFII flox/flox mice is not perturbed, suggesting that the rostral half of the tympanic ring is sufficient to support proper MM development. Interestingly, we found that loss of COUP-TFII up-regulates Sox9 in the tympanic ring primordium and affects the distribution of preosteoblasts before mesenchymal condensation. Together, our results demonstrate that COUP-TFII plays an essential role in regulating the patterning of the NCC-derived tympanic ring
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Endocardial Cushion Morphogenesis and Coronary Vessel Development Require Chicken Ovalbumin Upstream Promoter-Transcription Factor II
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Fu-jung Lin, Ming-jer Tsai, Li-ru You, Wen-hsin Hsu, Sophia Y. TsaiAbstract:Objective— Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis. Methods and Results— We analyzed embryos deficient in COUP-TFII and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific COUP-TFII mutants and molecular approaches, we show that COUP-TFII deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of Snai1 , one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation. Conclusion— Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.
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mouse lacking coup tfii as an animal model of bochdalek type congenital diaphragmatic hernia
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Li-ru You, Sophia Y. Tsai, Francesco J Demayo, Norio Takamoto, Toshiya Tanaka, Tatsuhiko Kodama, Ming-jer TsaiAbstract:Congenital diaphragmatic hernia (CDH), a life-threatening anomaly, is a major cause of pediatric mortality. Although the disease was described >350 years ago, the etiology of CDH is poorly understood. Here, we show that tissue-specific null mutants of COUP-TFII exhibit Bochdalek-type CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the posthepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Thus, both the stomach and liver enter the thoracic cavity, leading to lung hypoplasia and neonatal death. Recently a minimally deleted region for CDH has been identified on chromosome 15q26.1-26.2 by CGH array and FISH analysis. COUP-TFII is one of the four known genes residing within this critical region. Our finding suggests that COUP-TFII is a likely contributor to the formation of CDH in individuals with 15q deletions, and it may also be a potential contributor to some other Bochdalek-type of CDH.
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suppression of notch signalling by the coup tfii transcription factor regulates vein identity
Nature, 2005Co-Authors: Li-ru You, Ming-jer Tsai, Fu-jung Lin, Christopher T Lee, Francesco J Demayo, Sophia Y. TsaiAbstract:Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial-venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor--Flk1 and neuropilin 1 (NP-1; also called Nrp1)--activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.
Evan D Rosen - One of the best experts on this subject based on the ideXlab platform.
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the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor ii is a critical regulator of adipogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Chung Hsin Hsu, Jun Eguchi, Evan D RosenAbstract:The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; Nr2f2) is expressed in adipose tissue in vivo and declines during differentiation. Overexpression of COUP-TFII prevents adipogenesis, whereas shRNA-mediated reduction of COUP-TFII promotes differentiation, as shown by increased lipid accumulation and elevated expression of fat cell marker proteins. Furthermore, reduction of COUP-TFII allows uncommitted fibroblasts to be differentiated into fat cells. COUP-TFII represses the expression of a number of proadipogenic factors in adipocytes, with direct action noted at the CAAT enhancer-binding protein α promoter. We show that COUP-TFII acts downstream of hedgehog signaling and is required for the full antiadipogenic effect of this pathway. This effect is mediated in part by interaction with GATA factors. COUP-TFII and GATA2 are physically associated and repress target gene expression in an additive manner. Taken together, our data demonstrate that COUP-TFII represents an endogenous suppressor of adipogenesis, linking antiadipogenic extracellular signals to the core transcriptional cascade.
Francesco J Demayo - One of the best experts on this subject based on the ideXlab platform.
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generation of es cells for conditional expression of nuclear receptors and coregulators in vivo
Molecular Endocrinology, 2010Co-Authors: Dongkee Lee, Sophia Y. Tsai, Francesco J Demayo, Ming-jer TsaiAbstract:Nuclear receptors and coregulators orchestrate diverse aspects of biological functions and inappropriate expression of these factors often associates with human diseases. The present study describes a conditional overexpression system consisting of a minigene located at the Rosa26 locus in the genome of mouse embryonic stem (ES) cells. Before activation, the minigene is silent due to a floxed STOP cassette inserted between the promoter and the transgene. Upon cre-mediated excision of the STOP cassette, the minigene constitutively expresses the tagged transgene driven by the ubiquitous CAGGS promoter. Thus, this system can be used to express target gene in any tissue in a spatial and/or temporal manner if respective cre mouse lines are available. Serving as proof of principle, the CAG-S-hCOUP-TFI allele was generated in ES cells and subsequently in mice. This allele was capable of conditionally overexpressing human chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) in all tissues tested upon activation by cre drivers. This allele was further subjected to address functionality of expressed COUP-TFI and the functional similarity between COUP-TFI and COUP-TFII. Expression of COUP-TFI in COUP-TFII-ablated uterus suppressed aberrant estrogen receptor-α activities and rescued implantation and decidualization defects of COUP-TFII mutants, suggesting that COUP-TFI and COUP-TFII are able to functionally compensate for each other in the uterus. A toolbox currently under construction will contain ES cell lines for overexpressing all 48 nuclear receptors and selected 10 coregulators. Upon completion, it will be a very valuable resource for the scientific community. Several ES cells are currently available for distribution.
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mouse lacking coup tfii as an animal model of bochdalek type congenital diaphragmatic hernia
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Li-ru You, Sophia Y. Tsai, Francesco J Demayo, Norio Takamoto, Toshiya Tanaka, Tatsuhiko Kodama, Ming-jer TsaiAbstract:Congenital diaphragmatic hernia (CDH), a life-threatening anomaly, is a major cause of pediatric mortality. Although the disease was described >350 years ago, the etiology of CDH is poorly understood. Here, we show that tissue-specific null mutants of COUP-TFII exhibit Bochdalek-type CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the posthepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Thus, both the stomach and liver enter the thoracic cavity, leading to lung hypoplasia and neonatal death. Recently a minimally deleted region for CDH has been identified on chromosome 15q26.1-26.2 by CGH array and FISH analysis. COUP-TFII is one of the four known genes residing within this critical region. Our finding suggests that COUP-TFII is a likely contributor to the formation of CDH in individuals with 15q deletions, and it may also be a potential contributor to some other Bochdalek-type of CDH.
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suppression of notch signalling by the coup tfii transcription factor regulates vein identity
Nature, 2005Co-Authors: Li-ru You, Ming-jer Tsai, Fu-jung Lin, Christopher T Lee, Francesco J Demayo, Sophia Y. TsaiAbstract:Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial-venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor--Flk1 and neuropilin 1 (NP-1; also called Nrp1)--activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.
