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Kiyotoshi Sekiguchi - One of the best experts on this subject based on the ideXlab platform.
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basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser Syndrome associated proteins
Journal of Cell Biology, 2012Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Makiko Takeichi, Yuya Sato, Tomohiko Fukuda, Kiyotoshi SekiguchiAbstract:Dysfunction of the basement membrane protein QBRICK provokes Fraser Syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1–dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser Syndrome.
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Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser Syndrome–associated proteins
The Journal of cell biology, 2012Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Makiko Takeichi, Yuya Sato, Tomohiko Fukuda, Kiyotoshi SekiguchiAbstract:Dysfunction of the basement membrane protein QBRICK provokes Fraser Syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1–dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser Syndrome.
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Fused pulmonary lobes is a rat model of human Fraser Syndrome.
Biochemical and biophysical research communications, 2011Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Ken L. Takahashi, Hitoshi Hojo, Hiroaki Aoyama, Kiyotoshi SekiguchiAbstract:Fused pulmonary lobes (fpl) is a mutant gene that is inherited in an autosomal recessive manner and causes various developmental defects, including fusion of pulmonary lobes, and eyelid and digit anomalies in rats. Since these developmental defects closely resemble those observed in patients with Fraser Syndrome, a recessive multiorgan disorder, and its model animals, we investigated whether the abnormal phenotypes observed in fpl/fpl mutant rats are attributable to a genetic disorder similar to Fraser Syndrome. At the epidermal basement membrane in fpl/fpl mutant neonates, the expression of QBRICK, a basement membrane protein whose expression is attenuated in Fraser Syndrome model mice, was greatly diminished compared with control littermates. Quantitative RT-PCR analyses of Fraser Syndrome-related genes revealed that Frem2 transcripts were markedly diminished in QBRICK-negative embryos. Genomic DNA sequencing of the fpl/fpl mutant identified a nonsense mutation that introduced a stop codon at serine 2005 in Frem2. These findings indicate that the fpl mutant is a rat model of human Fraser Syndrome.
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breakdown of the reciprocal stabilization of qbrick frem1 fras1 and frem2 at the basement membrane provokes Fraser Syndrome like defects
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Daiji Kiyozumi, Nagisa Sugimoto, Kiyotoshi SekiguchiAbstract:An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-β motif(s) includes Fras1, QBRICK/Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser Syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser Syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK/Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser Syndrome model mouse, in which GRIP1, a Fras1- and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick/Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser Syndrome phenotypes with defective epidermal–dermal interactions, the coordinated assembly of three Fraser Syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal–dermal interactions during morphogenetic processes.
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Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser Syndrome-like defects
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Daiji Kiyozumi, Nagisa Sugimoto, Kiyotoshi SekiguchiAbstract:An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-β motif(s) includes Fras1, QBRICK/Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser Syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser Syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK/Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser Syndrome model mouse, in which GRIP1, a Fras1- and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick/Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser Syndrome phenotypes with defective epidermal–dermal interactions, the coordinated assembly of three Fraser Syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal–dermal interactions during morphogenetic processes.
Daiji Kiyozumi - One of the best experts on this subject based on the ideXlab platform.
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basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser Syndrome associated proteins
Journal of Cell Biology, 2012Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Makiko Takeichi, Yuya Sato, Tomohiko Fukuda, Kiyotoshi SekiguchiAbstract:Dysfunction of the basement membrane protein QBRICK provokes Fraser Syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1–dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser Syndrome.
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Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser Syndrome–associated proteins
The Journal of cell biology, 2012Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Makiko Takeichi, Yuya Sato, Tomohiko Fukuda, Kiyotoshi SekiguchiAbstract:Dysfunction of the basement membrane protein QBRICK provokes Fraser Syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1–dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser Syndrome.
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Fused pulmonary lobes is a rat model of human Fraser Syndrome.
Biochemical and biophysical research communications, 2011Co-Authors: Daiji Kiyozumi, Itsuko Nakano, Ken L. Takahashi, Hitoshi Hojo, Hiroaki Aoyama, Kiyotoshi SekiguchiAbstract:Fused pulmonary lobes (fpl) is a mutant gene that is inherited in an autosomal recessive manner and causes various developmental defects, including fusion of pulmonary lobes, and eyelid and digit anomalies in rats. Since these developmental defects closely resemble those observed in patients with Fraser Syndrome, a recessive multiorgan disorder, and its model animals, we investigated whether the abnormal phenotypes observed in fpl/fpl mutant rats are attributable to a genetic disorder similar to Fraser Syndrome. At the epidermal basement membrane in fpl/fpl mutant neonates, the expression of QBRICK, a basement membrane protein whose expression is attenuated in Fraser Syndrome model mice, was greatly diminished compared with control littermates. Quantitative RT-PCR analyses of Fraser Syndrome-related genes revealed that Frem2 transcripts were markedly diminished in QBRICK-negative embryos. Genomic DNA sequencing of the fpl/fpl mutant identified a nonsense mutation that introduced a stop codon at serine 2005 in Frem2. These findings indicate that the fpl mutant is a rat model of human Fraser Syndrome.
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breakdown of the reciprocal stabilization of qbrick frem1 fras1 and frem2 at the basement membrane provokes Fraser Syndrome like defects
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Daiji Kiyozumi, Nagisa Sugimoto, Kiyotoshi SekiguchiAbstract:An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-β motif(s) includes Fras1, QBRICK/Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser Syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser Syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK/Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser Syndrome model mouse, in which GRIP1, a Fras1- and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick/Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser Syndrome phenotypes with defective epidermal–dermal interactions, the coordinated assembly of three Fraser Syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal–dermal interactions during morphogenetic processes.
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Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser Syndrome-like defects
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Daiji Kiyozumi, Nagisa Sugimoto, Kiyotoshi SekiguchiAbstract:An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-β motif(s) includes Fras1, QBRICK/Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser Syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser Syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK/Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser Syndrome model mouse, in which GRIP1, a Fras1- and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick/Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser Syndrome phenotypes with defective epidermal–dermal interactions, the coordinated assembly of three Fraser Syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal–dermal interactions during morphogenetic processes.
Jason Hopkins - One of the best experts on this subject based on the ideXlab platform.
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Identification of a new gene mutated in Fraser Syndrome and mouse myelencephalic blebs
Nature Genetics, 2005Co-Authors: Shalini Jadeja, Georges Chalepakis, Ian Smyth, Jolanta E Pitera, Martin S Taylor, Mieke Van Haelst, Elizabeth Bentley, Lesley Mcgregor, Jason Hopkins, Nicole PhilipAbstract:Fraser Syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects^ 1 , 2 and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs ( my ) strain has a similar phenotype. We mapped my to Frem2 , a gene related to Fras1 and Frem1 , and showed that a Frem2 gene-trap mutation was allelic to my . Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser Syndrome were homozygous with respect to the same missense mutation of FREM2 , confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser Syndrome, suggesting that calcium binding in the CALXβ-cadherin motif is important for normal functioning of FREM2 .
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Identification of a new gene mutated in Fraser Syndrome and mouse myelencephalic blebs.
Nature genetics, 2005Co-Authors: Shalini Jadeja, Georges Chalepakis, Jolanta E Pitera, Martin S Taylor, Elizabeth Bentley, Jason Hopkins, Ian M. Smyth, Mieke M. Van Haelst, Lesley M Mcgregor, Nicole PhilipAbstract:Fraser Syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser Syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser Syndrome, suggesting that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2.
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Fraser Syndrome and mouse blebbed phenotype caused by mutations in fras1 fras1 encoding a putative extracellular matrix protein
Nature Genetics, 2003Co-Authors: Lesley M Mcgregor, Georges Chalepakis, Vile Makela, Susan M Darling, Sofia Vrontou, Catherine Roberts, Nicola Smart, Paul Rutland, Natalie J Prescott, Jason HopkinsAbstract:Fraser Syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects(1). Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser Syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser Syndrome is a human equivalent of the blebbed phenotype in the mouse(2), which has been associated with mutations in at least five loci including bl(3). As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser Syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.
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Fraser Syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein
Nature Genetics, 2003Co-Authors: Lesley Mcgregor, Georges Chalepakis, Susan M Darling, Sofia Vrontou, Catherine Roberts, Nicola Smart, Paul Rutland, Ville Makela, Natalie Prescott, Jason HopkinsAbstract:Fraser Syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects^ 1 . Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser Syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1 , which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser Syndrome is a human equivalent of the blebbed phenotype in the mouse^ 2 , which has been associated with mutations in at least five loci including bl ^ 3 . As mapping data were consistent with homology of FRAS1 and bl , we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1 . Thus, the bl mouse is a model for Fraser Syndrome in humans, a disorder caused by disrupted epithelial integrity in utero .
Peter J. Scambler - One of the best experts on this subject based on the ideXlab platform.
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sprouty1 haploinsufficiency prevents renal agenesis in a model of Fraser Syndrome
Journal of The American Society of Nephrology, 2012Co-Authors: Jolanta E Pitera, Adrian S. Woolf, Albert M Basson, Peter J. ScamblerAbstract:Deficiency of the extracellular matrix molecule FRAS1, normally expressed by the ureteric bud, leads to bilateral renal agenesis in humans with Fraser Syndrome and blebbed ( Fras1 bl/bl ) mice. The metanephric mesenchyme of these mutants fails to express sufficient Gdnf , which activates receptor tyrosine kinase (RTK) signalling, contributing to the phenotype. To determine whether modulating RTK signalling may overcome the abnormal nephrogenesis characteristic of Fraser Syndrome, we introduced a single null Sprouty1 allele into Fras1 bl/bl mice, thereby reducing the ureteric bud9s expression of this anti-branching molecule and antagonist of RTK signalling. This prevented renal agenesis in Fras1 bl/bl mice, permitting kidney development and postnatal survival. We found that fibroblast growth factor (FGF) signalling contributed to this genetic rescue, and exogenous FGF10 rescued defects in Fras1 bl/bl rudiments in vitro . Whereas wild-type metanephroi expressed FRAS1 and the related proteins FREM1 and FREM2, FRAS1 was absent and the other proteins were downregulated in rescued kidneys, consistent with a reciprocally stabilized FRAS1/FREM1/FREM2 complex. In addition to contributing to knowledge regarding events during nephrogenesis, the demonstrated rescue of renal agenesis in a model of a human genetic disease raises the possibility that enhancing growth factor signaling might be a therapeutic approach to ameliorate this devastating malformation.
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Generation of mice with a conditional null Fraser Syndrome 1 (Fras1) allele
Genesis (New York N.Y. : 2000), 2012Co-Authors: Jolanta E Pitera, Adrian S. Woolf, Mark Turmaine, Peter J. ScamblerAbstract:Summary: Fraser Syndrome (FS) is an autosomal recessive disease characterized by skin lesions and kidney and upper airway malformations. Fraser Syndrome 1 (FRAS1) is an extracellular matrix protein, and FRAS1 homozygous mutations occur in some FS individuals. FRAS1is expressed at the epithelial-mesenchymal interface in embryonic skin and kidney. blebbed mice have a null Fras1 mutation and phenocopy human FS. Like humans with FS, they exhibit a high fetal and neonatal mortality, precluding studies of FRAS1 functions in later life. We generated conditional Fras1 null allele mice. Cre-mediated generalized deletion of this allele generated embryonic skin blisters and renal agenesis characteristic of blebbed mice and human FS. Targeted deletion of Fras1 in kidney podocytes circumvented skin blistering, renal agenesis, and early death. FRAS1 expression was downregulated in maturing glomeruli which then became sclerotic. The data are consistent with the hypothesis that locally produced FRAS1 has roles in glomerular maturation and integrity. This conditional allele will facilitate study of possible role for FRAS1 in other tissues such as the skin. genesis 50:892–898, 2012. © 2012 Wiley Periodicals, Inc.
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Expression of Fraser Syndrome genes in normal and polycystic murine kidneys
Pediatric Nephrology, 2012Co-Authors: Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, David A. Long, Adrian S. WoolfAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 ( Fraser Syndrome 1 ) and FREM2 ( FRAS1-related extracellular matrix protein 2 ) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys. Methods In healthy and congenital polycystic kidney ( cpk ) mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK ( Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wild-type metanephroi rendered cystic by dexamethasone. Results Nascent nephrons transiently expressed Frem2 in both tubule and podocyte epithelia. Maturing and adult collecting ducts also expressed Frem2 . Frem2 was expressed in cpk cystic epithelia although Frem2 haploinsufficiency did not significantly modify cystogenesis in vivo. Fras1 transcripts were significantly upregulated, and Frem3 downregulated, in polycystic kidneys versus the non-cystic kidneys of littermates. Fras1 was immunodetected in cpk , PCK and dexamethasone-induced cyst epithelia. Conclusions These descriptive results are consistent with the hypothesis that Fras family molecules play diverse roles in kidney epithelia. In future, this should be tested by conditional deletion of FS genes in nephron segments and collecting ducts.
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DOI 10.1007/s00467-012-2100-5 ORIGINAL ARTICLE Expression of Fraser Syndrome genes in normal and polycystic murine kidneys
2012Co-Authors: PJ Scambler, Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, Adrian S. Woolf, David A. Long, Zahabia AliAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser Syndrome 1) and FREM2 (FRAS1-related extracellular matrix protein 2) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys. Methods In healthy and congenital polycystic kidney (cpk) mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK (Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wildtype metanephroi rendered cystic by dexamethasone
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Expression of Fraser Syndrome genes in normal and polycystic murine kidneys.
Pediatric nephrology (Berlin Germany), 2011Co-Authors: Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, David A. Long, Zahabia Ali, Adrian S. WoolfAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser Syndrome 1) and FREM2 (FRAS1-related extracellular matrix protein 2) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys.
Adrian S. Woolf - One of the best experts on this subject based on the ideXlab platform.
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sprouty1 haploinsufficiency prevents renal agenesis in a model of Fraser Syndrome
Journal of The American Society of Nephrology, 2012Co-Authors: Jolanta E Pitera, Adrian S. Woolf, Albert M Basson, Peter J. ScamblerAbstract:Deficiency of the extracellular matrix molecule FRAS1, normally expressed by the ureteric bud, leads to bilateral renal agenesis in humans with Fraser Syndrome and blebbed ( Fras1 bl/bl ) mice. The metanephric mesenchyme of these mutants fails to express sufficient Gdnf , which activates receptor tyrosine kinase (RTK) signalling, contributing to the phenotype. To determine whether modulating RTK signalling may overcome the abnormal nephrogenesis characteristic of Fraser Syndrome, we introduced a single null Sprouty1 allele into Fras1 bl/bl mice, thereby reducing the ureteric bud9s expression of this anti-branching molecule and antagonist of RTK signalling. This prevented renal agenesis in Fras1 bl/bl mice, permitting kidney development and postnatal survival. We found that fibroblast growth factor (FGF) signalling contributed to this genetic rescue, and exogenous FGF10 rescued defects in Fras1 bl/bl rudiments in vitro . Whereas wild-type metanephroi expressed FRAS1 and the related proteins FREM1 and FREM2, FRAS1 was absent and the other proteins were downregulated in rescued kidneys, consistent with a reciprocally stabilized FRAS1/FREM1/FREM2 complex. In addition to contributing to knowledge regarding events during nephrogenesis, the demonstrated rescue of renal agenesis in a model of a human genetic disease raises the possibility that enhancing growth factor signaling might be a therapeutic approach to ameliorate this devastating malformation.
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Generation of mice with a conditional null Fraser Syndrome 1 (Fras1) allele
Genesis (New York N.Y. : 2000), 2012Co-Authors: Jolanta E Pitera, Adrian S. Woolf, Mark Turmaine, Peter J. ScamblerAbstract:Summary: Fraser Syndrome (FS) is an autosomal recessive disease characterized by skin lesions and kidney and upper airway malformations. Fraser Syndrome 1 (FRAS1) is an extracellular matrix protein, and FRAS1 homozygous mutations occur in some FS individuals. FRAS1is expressed at the epithelial-mesenchymal interface in embryonic skin and kidney. blebbed mice have a null Fras1 mutation and phenocopy human FS. Like humans with FS, they exhibit a high fetal and neonatal mortality, precluding studies of FRAS1 functions in later life. We generated conditional Fras1 null allele mice. Cre-mediated generalized deletion of this allele generated embryonic skin blisters and renal agenesis characteristic of blebbed mice and human FS. Targeted deletion of Fras1 in kidney podocytes circumvented skin blistering, renal agenesis, and early death. FRAS1 expression was downregulated in maturing glomeruli which then became sclerotic. The data are consistent with the hypothesis that locally produced FRAS1 has roles in glomerular maturation and integrity. This conditional allele will facilitate study of possible role for FRAS1 in other tissues such as the skin. genesis 50:892–898, 2012. © 2012 Wiley Periodicals, Inc.
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Expression of Fraser Syndrome genes in normal and polycystic murine kidneys
Pediatric Nephrology, 2012Co-Authors: Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, David A. Long, Adrian S. WoolfAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 ( Fraser Syndrome 1 ) and FREM2 ( FRAS1-related extracellular matrix protein 2 ) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys. Methods In healthy and congenital polycystic kidney ( cpk ) mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK ( Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wild-type metanephroi rendered cystic by dexamethasone. Results Nascent nephrons transiently expressed Frem2 in both tubule and podocyte epithelia. Maturing and adult collecting ducts also expressed Frem2 . Frem2 was expressed in cpk cystic epithelia although Frem2 haploinsufficiency did not significantly modify cystogenesis in vivo. Fras1 transcripts were significantly upregulated, and Frem3 downregulated, in polycystic kidneys versus the non-cystic kidneys of littermates. Fras1 was immunodetected in cpk , PCK and dexamethasone-induced cyst epithelia. Conclusions These descriptive results are consistent with the hypothesis that Fras family molecules play diverse roles in kidney epithelia. In future, this should be tested by conditional deletion of FS genes in nephron segments and collecting ducts.
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DOI 10.1007/s00467-012-2100-5 ORIGINAL ARTICLE Expression of Fraser Syndrome genes in normal and polycystic murine kidneys
2012Co-Authors: PJ Scambler, Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, Adrian S. Woolf, David A. Long, Zahabia AliAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser Syndrome 1) and FREM2 (FRAS1-related extracellular matrix protein 2) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys. Methods In healthy and congenital polycystic kidney (cpk) mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK (Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wildtype metanephroi rendered cystic by dexamethasone
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Expression of Fraser Syndrome genes in normal and polycystic murine kidneys.
Pediatric nephrology (Berlin Germany), 2011Co-Authors: Larissa Kerecuk, Corina Anders, Maria Kolatsi-joannou, Peter J. Scambler, David A. Long, Zahabia Ali, Adrian S. WoolfAbstract:Background Fraser Syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser Syndrome 1) and FREM2 (FRAS1-related extracellular matrix protein 2) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys.
