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Albert Hofman - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing and functional analyses suggest that six6 is a gene involved in an altered proliferation differentiation balance early in life and optic nerve degeneration at old age
Human Molecular Genetics, 2014Co-Authors: Adriana I Iglesias, Henriet Springelkamp, Christel E M Kockx, Lies-anne Severijnen, Herma C Van Der Linde, Marie Claire Van Hout, Najaf Amin, Wilfred F J Van Ijcken, Ben A. Oostra, Albert HofmanAbstract:textabstractPrimary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10-7, n = 11 473) and POAG (Pmeta = 6.09 × 10-3, n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10-3, n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
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exome sequencing and functional analyses suggest that six6 is a gene involved in an altered proliferation differentiation balance early in life and optic nerve degeneration at old age
Human Molecular Genetics, 2014Co-Authors: Adriana I Iglesias, Henriet Springelkamp, Christel E M Kockx, Lies-anne Severijnen, Najaf Amin, Ben A. Oostra, Herma C Van Der Linde, Mirjam C G N Van Den Hout, Wilfred F J Van Ijcken, Albert HofmanAbstract:Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10-7, n = 11 473) and POAG (Pmeta = 6.09 × 10-3, n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10-3, n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
Stephen J Tapscott - One of the best experts on this subject based on the ideXlab platform.
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ctcf binding sites flank ctg cag repeats and form a methylation sensitive insulator at the dm1 locus
Nature Genetics, 2001Co-Authors: Galina N Filippova, Diane H Cho, Cortlandt P Thienes, Stephen J Tapscott, Bennett H Penn, James M Moore, Todd R Klesert, Victor V LobanenkovAbstract:An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy (DM) by altering the expression of the two adjacent genes, DMPK and SIX5, and through a toxic effect of the repeat-containing RNA. Here we identify two CTCF-binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital DM would disrupt insulator function. Furthermore, CTCF-binding sites are associated with CTG/CAG repeats at several other loci. We suggest a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome.
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Mice deficient in SIX5 develop cataracts: implications for myotonic dystrophy
Nature Genetics, 2000Co-Authors: Todd R Klesert, Diane H Cho, John I. Clark, James Maylie, John Adelman, Lauren Snider, Eric C. Yuen, Philippe Soriano, Stephen J TapscottAbstract:Expansion of a CTG trinucleotide repeat in the 3′ UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy^ 1 , 2 , 3 , a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15 , the mouse orthologue of human DMPK , produced mice with a mild myopathy^ 4 , 5 and cardiac conduction abnormalities^ 6 , but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7 , 8 ), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse SIX5 by replacing the first exon with a β-galactosidase reporter. SIX5 -mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.
Adriana I Iglesias - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing and functional analyses suggest that six6 is a gene involved in an altered proliferation differentiation balance early in life and optic nerve degeneration at old age
Human Molecular Genetics, 2014Co-Authors: Adriana I Iglesias, Henriet Springelkamp, Christel E M Kockx, Lies-anne Severijnen, Herma C Van Der Linde, Marie Claire Van Hout, Najaf Amin, Wilfred F J Van Ijcken, Ben A. Oostra, Albert HofmanAbstract:textabstractPrimary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10-7, n = 11 473) and POAG (Pmeta = 6.09 × 10-3, n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10-3, n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
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exome sequencing and functional analyses suggest that six6 is a gene involved in an altered proliferation differentiation balance early in life and optic nerve degeneration at old age
Human Molecular Genetics, 2014Co-Authors: Adriana I Iglesias, Henriet Springelkamp, Christel E M Kockx, Lies-anne Severijnen, Najaf Amin, Ben A. Oostra, Herma C Van Der Linde, Mirjam C G N Van Den Hout, Wilfred F J Van Ijcken, Albert HofmanAbstract:Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10-7, n = 11 473) and POAG (Pmeta = 6.09 × 10-3, n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10-3, n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
Noriko Osumi - One of the best experts on this subject based on the ideXlab platform.
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dynamic expression of six family genes in the dental mesenchyme and the epithelial ameloblast stem progenitor cells during murine tooth development
Journal of Anatomy, 2010Co-Authors: Koji Nonomura, Masanori Takahashi, Yoshio Wakamatsu, Teruko Takanoyamamoto, Noriko OsumiAbstract:Six family transcription factor genes play multiple and crucial roles in the development of the vertebrate sensory system including the eye, olfactory epithelium and otic vesicle, and these genes are highly expressed in the neural crest-derived cranial mesenchymal cells in the mouse embryo. However, expression patterns have yet to be determined for the Six family genes in the developing tooth germ. In this study, we examined expression of six members of the Six family genes in the dental mesenchyme and the dental epithelium of the developing tooth germs in mice by in situ hybridization. We found dynamic expression patterns for Six1, Six2, Six4 and SIX5 in the oral epithelium and mesenchymal cells with distinct expression patterns at the early stage before invagination of the dental epithelium. In addition, expression of Six1 and Six4 was observed in the inner enamel epithelium of the incisor and molar tooth germs at the cap stage. Expression of SIX5 was maintained in the bell stage tooth germs, and intense expression of Six1 and Six4 was detected not only in the mesenchyme-derived dental follicle but also in the proliferating inner enamel epithelium of the labial cervical loop of the incisor tooth germ. Taken together, our results suggest that dynamic expression of Six family genes represents specific stages of the developing tooth germ. This dynamic expression is embodied in changes in both space and over time, and these changes in expression suggest that Six family genes may participate in tooth germ morphogenesis and the proliferation and/or differentiation of the incisor ameloblast stem/progenitor cells.
Pascal Maire - One of the best experts on this subject based on the ideXlab platform.
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Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development.
Journal of dental research, 2019Co-Authors: Z. Liu, Pascal Maire, Yu Lan, Han Liu, X. Wang, Rulang JiangAbstract:SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1 -/- Six2 -/- double-mutant mice were born with severe craniofacial deformity not seen in the Six1 -/- or Six2 -/- single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1 -/- mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1 -/-Six2 +/- mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1 -/- embryos, the E10.5 Six1 -/- Six2 +/- embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 -/- and Six1 -/- Six2 +/- embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest-specific inactivation of Six1 in Six2 -/- embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1 -/- Six2 -/- embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell-autonomous role in frontonasal morphogenesis.
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Six1 and Six4 gene expression is necessary to activate the fast-type muscle gene program in the mouse primary myotome
Developmental Biology, 2010Co-Authors: Claire Niro, Josiane Demignon, Stéphane Vincent, Yubing Liu, Julien Giordani, Nicolas Sgarioto, Maryline Favier, Isabelle Guillet-deniau, Alexandre Blais, Pascal MaireAbstract:While the signaling pathways and transcription factors active in adult slow- and fast-type muscles begin to be characterized, genesis of muscle fiber-type diversity during mammalian development remains unexplained. We provide evidence showing that Six homeoproteins are required to activate the fast-type muscle program in the mouse primary myotome. Affymetrix transcriptomal analysis of Six1(-/-)Six4(-/-) E10.5 somites revealed the specific down-regulation of many genes of the fast-type muscle program. This data was confirmed by in situ hybridization performed on Six1(-/-)Six4(-/-) embryos. The first mouse myocytes express both fast-type and slow-type muscle genes. In these fibers, Six1 and Six4 expression is required to specifically activate fast-type muscle genes. Chromatin immunoprecipitation experiments confirm the binding of Six1 and Six4 on the regulatory regions of these muscle genes, and transfection experiments show the ability of these homeoproteins to activate specifically identified fast-type muscle genes. This in vivo wide transcriptomal analysis of the function of the master myogenic determinants, Six, identifies them as novel markers for the differential activation of a specific muscle program during mammalian somitic myogenesis.
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patterning of the third pharyngeal pouch into thymus parathyroid by six and eya1
Developmental Biology, 2006Co-Authors: Dan Zou, Derek Silvius, Raphaelle Grifone, Julie Davenport, Pascal MaireAbstract:Previous studies have suggested a role of the homeodomain Six family proteins in patterning the developing vertebrate head that involves appropriate segmentation of three tissue layers, the endoderm, the paraxial mesoderm and the neural crest cells; however, the developmental programs and mechanisms by which the Six genes act in the pharyngeal endoderm remain largely unknown. Here, we examined their roles in pharyngeal pouch development. Six1−/− mice lack thymus and parathyroid and analysis of Six1−/− third pouch endoderm demonstrated that the patterning of the third pouch into thymus/parathyroid primordia is initiated. However, the endodermal cells of the thymus/parathyroid rudiments fail to maintain the expression of the parathyroid-specific gene Gcm2 and the thymus-specific gene Foxn1 and subsequently undergo abnormal apoptosis, leading to a complete disappearance of organ primordia by E12.5. This thus defines the thymus/parathyroid defects present in the Six1 mutant. Analyses of the thymus/parathyroid development in Six1−/−;Six4−/− double mutant show that both Six1 and Six4 act synergistically to control morphogenetic movements of early thymus/parathyroid tissues, and the threshold of Six1/Six4 appears to be crucial for the regulation of the organ primordia-specific gene expression. Previous studies in flies and mice suggested that Eya and Six genes may function downstream of Pax genes. Our data clearly show that Eya1 and Six1 expression in the pouches does not require Pax1/Pax9 function, suggesting that they may function independently from Pax1/Pax9. In contrast, Pax1 expression in all pharyngeal pouches requires both Eya1 and Six1 function. Moreover, we show that the expression of Tbx1, Fgf8 and Wnt5b in the pouch endoderm was normal in Six1−/− embryos and slightly reduced in Six1−/−;Six4−/− double mutant, but was largely reduced in Eya1−/− embryos. These results indicate that Eya1 appears to be upstream of very early events in the initiation of thymus/parathyroid organogenesis, while Six genes appear to act in an early differentiation step during thymus/parathyroid morphogenesis. Together, these analyses establish an essential role for Eya1 and Six genes in patterning the third pouch into organ-specific primordia.
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six1 and six4 homeoproteins are required for pax3 and mrf expression during myogenesis in the mouse embryo
Development, 2005Co-Authors: Raphaelle Grifone, Mary J. Seller, Josiane Demignon, Christophe Houbron, Evelyne Souil, Claire Niro, Ghislaine Hamard, Pascal MaireAbstract:In mammals, SIX5, Six4 and Six1 genes are co-expressed during mouse myogenesis. Six4 and SIX5 single knockout (KO) mice have no developmental defects, while Six1 KO mice die at birth and show multiple organ developmental defects. We have generated Six1Six4 double KO mice and show an aggravation of the phenotype previously reported for the single Six1 KO. Six1Six4 double KO mice are characterized by severe craniofacial and rib defects, and general muscle hypoplasia. At the limb bud level, Six1 and Six4 homeogenes control early steps of myogenic cell delamination and migration from the somite through the control of Pax3 gene expression. Impaired in their migratory pathway, cells of the somitic ventrolateral dermomyotome are rerouted, lose their identity and die by apoptosis. At the interlimb level, epaxial Met expression is abolished, while it is preserved in Pax3 -deficient embryos. Within the myotome, absence of Six1 and Six4 impairs the expression of the myogenic regulatory factors myogenin and Myod1, and Mrf4 expression becomes undetectable. Myf5 expression is correctly initiated but becomes restricted to the caudal region of each somite. Early syndetomal expression of scleraxis is reduced in the Six1Six4 embryo, while the myotomal expression of Fgfr4 and Fgf8 but not Fgf4 and Fgf6 is maintained. These results highlight the different roles played by Six proteins during skeletal myogenesis.
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six1 is required for the early organogenesis of mammalian kidney
Development, 2003Co-Authors: Pinxian Xu, Weiming Zheng, Christine Laclef, Li Huang, Pascal Maire, Derek SilviusAbstract:The murine Six gene family, homologous to Drosophila sine oculis ( so ) which encodes a homeodomain transcription factor, is composed of six members ( Six1-6 ). Among the six members, only the Six2 gene has been previously shown to be expressed early in kidney development, but its function is unknown. We have recently found that the Six1 gene is also expressed in the kidney. In the developing kidney, Six1 is expressed in the uninduced metanephric mesenchyme at E10.5 and in the induced mesenchyme around the ureteric bud at E11.5. At E17.5 to P0, Six1 expression became restricted to a subpopulation of collecting tubule epithelial cells. To study its in vivo function, we have recently generated Six1 mutant mice. Loss of Six1 leads to a failure of ureteric bud invasion into the mesenchyme and subsequent apoptosis of the mesenchyme. These results indicate that Six1 plays an essential role in early kidney development. In Six1 -/- kidney development, we have found that Pax2, Six2 and Sall1 expression was markedly reduced in the metanephric mesenchyme at E10.5, indicating that Six1 is required for the expression of these genes in the metanephric mesenchyme. In contrast, Eya1 expression was unaffected in Six1 -/- metanephric mesenchyme at E10.5, indicating that Eya1 may function upstream of Six1 . Moreover, our results show that both Eya1 and Six1 expression in the metanephric mesenchyme is preserved in Pax2 -/- embryos at E10.5, further indicating that Pax2 functions downstream of Eya1 and Six1 in the metanephric mesenchyme. Thus, the epistatic relationship between Pax, Eya and Six genes in the metanephric mesenchyme during early kidney development is distinct from a genetic pathway elucidated in the Drosophila eye imaginal disc. Finally, our results show that Eya1 and Six1 genetically interact during mammalian kidney development, because most compound heterozygous embryos show hypoplastic kidneys. These analyses establish a role for Six1 in the initial inductive step for metanephric development.