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  1. Article ; Online: Characterization of mouse Bmp5 regulatory injury element in zebrafish wound models.

    Heller, Ian S / Guenther, Catherine A / Meireles, Ana M / Talbot, William S / Kingsley, David M

    Bone

    2021  Volume 155, Page(s) 116263

    Abstract: Many key signaling molecules used to build tissues during embryonic development are re-activated at injury sites to stimulate tissue regeneration and repair. Bone morphogenetic proteins provide a classic example, but the mechanisms that lead to ... ...

    Abstract Many key signaling molecules used to build tissues during embryonic development are re-activated at injury sites to stimulate tissue regeneration and repair. Bone morphogenetic proteins provide a classic example, but the mechanisms that lead to reactivation of BMPs following injury are still unknown. Previous studies have mapped a large "injury response element" (IRE) in the mouse Bmp5 gene that drives gene expression following bone fractures and other types of injury. Here we show that the large mouse IRE region is also activated in both zebrafish tail resection and mechanosensory hair cell injury models. Using the ability to test multiple constructs and image temporal and spatial dynamics following injury responses, we have narrowed the original size of the mouse IRE region by over 100 fold and identified a small 142 bp minimal enhancer that is rapidly induced in both mesenchymal and epithelial tissues after injury. These studies identify a small sequence that responds to evolutionarily conserved local signals in wounded tissues and suggest candidate pathways that contribute to BMP reactivation after injury.
    MeSH term(s) Animals ; Bone Morphogenetic Proteins/metabolism ; Embryonic Development ; Mice ; Regulatory Sequences, Nucleic Acid ; Signal Transduction ; Zebrafish/genetics
    Chemical Substances Bone Morphogenetic Proteins
    Language English
    Publishing date 2021-11-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2021.116263
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A novel enhancer near the

    Thompson, Abbey C / Capellini, Terence D / Guenther, Catherine A / Chan, Yingguang Frank / Infante, Carlos R / Menke, Douglas B / Kingsley, David M

    eLife

    2018  Volume 7

    Abstract: Vertebrate pelvic reduction is a classic example of repeated evolution. Recurrent loss of pelvic appendages in sticklebacks has previously been linked to natural mutations in a pelvic enhancer that maps upstream ... ...

    Abstract Vertebrate pelvic reduction is a classic example of repeated evolution. Recurrent loss of pelvic appendages in sticklebacks has previously been linked to natural mutations in a pelvic enhancer that maps upstream of
    MeSH term(s) Animals ; Base Sequence ; Biological Evolution ; Chromosomes, Artificial, Bacterial/metabolism ; Conserved Sequence ; Enhancer Elements, Genetic ; Fishes/embryology ; Gene Expression Regulation, Developmental ; Genetic Loci ; Genome ; Hindlimb/growth & development ; Lizards/embryology ; Mice ; Paired Box Transcription Factors/genetics ; Paired Box Transcription Factors/metabolism ; Pelvis/growth & development ; Sequence Deletion ; Vertebrates/genetics ; Vertebrates/growth & development
    Chemical Substances Paired Box Transcription Factors ; homeobox protein PITX1
    Language English
    Publishing date 2018-11-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.38555
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A molecular basis for classic blond hair color in Europeans.

    Guenther, Catherine A / Tasic, Bosiljka / Luo, Liqun / Bedell, Mary A / Kingsley, David M

    Nature genetics

    2014  Volume 46, Issue 7, Page(s) 748–752

    Abstract: Hair color differences are among the most obvious examples of phenotypic variation in humans. Although genome-wide association studies (GWAS) have implicated multiple loci in human pigment variation, the causative base-pair changes are still largely ... ...

    Abstract Hair color differences are among the most obvious examples of phenotypic variation in humans. Although genome-wide association studies (GWAS) have implicated multiple loci in human pigment variation, the causative base-pair changes are still largely unknown. Here we dissect a regulatory region of the KITLG gene (encoding KIT ligand) that is significantly associated with common blond hair color in northern Europeans. Functional tests demonstrate that the region contains a regulatory enhancer that drives expression in developing hair follicles. This enhancer contains a common SNP (rs12821256) that alters a binding site for the lymphoid enhancer-binding factor 1 (LEF1) transcription factor, reducing LEF1 responsiveness and enhancer activity in cultured human keratinocytes. Mice carrying ancestral or derived variants of the human KITLG enhancer exhibit significant differences in hair pigmentation, confirming that altered regulation of an essential growth factor contributes to the classic blond hair phenotype found in northern Europeans.
    MeSH term(s) Animals ; Cells, Cultured ; Embryo, Mammalian/cytology ; Embryo, Mammalian/metabolism ; Enhancer Elements, Genetic/genetics ; Genome-Wide Association Study ; Hair Color/genetics ; Humans ; Keratinocytes/cytology ; Keratinocytes/metabolism ; Lymphoid Enhancer-Binding Factor 1/metabolism ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Skin Pigmentation/genetics ; Stem Cell Factor/genetics ; Whites/genetics
    Chemical Substances LEF1 protein, human ; Lymphoid Enhancer-Binding Factor 1 ; RNA, Messenger ; Stem Cell Factor
    Language English
    Publishing date 2014-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.2991
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3613: Show issues Location:
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  4. Article ; Online: Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins.

    Indjeian, Vahan B / Kingman, Garrett A / Jones, Felicity C / Guenther, Catherine A / Grimwood, Jane / Schmutz, Jeremy / Myers, Richard M / Kingsley, David M

    Cell

    2016  Volume 164, Issue 1-2, Page(s) 45–56

    Abstract: Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone-size differences in sticklebacks map ...

    Abstract Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone-size differences in sticklebacks map to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor-plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form.
    MeSH term(s) Adaptation, Physiological ; Animals ; Biological Evolution ; Enhancer Elements, Genetic ; Evolution, Molecular ; Fish Proteins/genetics ; Fish Proteins/metabolism ; Fresh Water ; Growth Differentiation Factor 6/genetics ; Growth Differentiation Factor 6/metabolism ; Humans ; Quantitative Trait Loci ; Seawater ; Skeleton/anatomy & histology ; Skeleton/physiology ; Smegmamorpha/genetics ; Smegmamorpha/physiology ; Species Specificity ; Vertebrates/classification ; Vertebrates/genetics ; Vertebrates/growth & development ; Vertebrates/metabolism
    Chemical Substances Fish Proteins ; Growth Differentiation Factor 6
    Language English
    Publishing date 2016-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2015.12.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1167: Show issues Location:
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    Zs.MG 58: Show issues

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  5. Article ; Online: The phosphate exporter xpr1b is required for differentiation of tissue-resident macrophages.

    Meireles, Ana M / Shiau, Celia E / Guenther, Catherine A / Sidik, Harwin / Kingsley, David M / Talbot, William S

    Cell reports

    2014  Volume 8, Issue 6, Page(s) 1659–1667

    Abstract: Phosphate concentration is tightly regulated at the cellular and organismal levels. The first metazoan phosphate exporter, XPR1, was recently identified, but its in vivo function remains unknown. In a genetic screen, we identified a mutation in a ... ...

    Abstract Phosphate concentration is tightly regulated at the cellular and organismal levels. The first metazoan phosphate exporter, XPR1, was recently identified, but its in vivo function remains unknown. In a genetic screen, we identified a mutation in a zebrafish ortholog of human XPR1, xpr1b. xpr1b mutants lack microglia, the specialized macrophages that reside in the brain, and also displayed an osteopetrotic phenotype characteristic of defects in osteoclast function. Transgenic expression studies indicated that xpr1b acts autonomously in developing macrophages. xpr1b mutants display no gross developmental defects that may arise from phosphate imbalance. We constructed a targeted mutation of xpr1a, a duplicate of xpr1b in the zebrafish genome, to determine whether Xpr1a and Xpr1b have redundant functions. Single mutants for xpr1a were viable, and double mutants for xpr1b;xpr1a were similar to xpr1b single mutants. Our genetic analysis reveals a specific role for the phosphate exporter Xpr1 in the differentiation of tissue macrophages.
    MeSH term(s) Animals ; Animals, Genetically Modified/metabolism ; Bone Development ; Bone Remodeling ; Brain/metabolism ; Cell Differentiation ; Embryo, Nonmammalian/metabolism ; Humans ; Macrophages/cytology ; Macrophages/metabolism ; Microglia/cytology ; Microglia/metabolism ; Mutation ; Phenotype ; Phosphates/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Virus/genetics ; Receptors, Virus/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Phosphates ; Protein Isoforms ; Receptors, G-Protein-Coupled ; Receptors, Virus ; Zebrafish Proteins ; xenotropic and polytropic retrovirus receptor
    Language English
    Publishing date 2014-09-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2014.08.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury.

    Guenther, Catherine A / Wang, Zhen / Li, Emma / Tran, Misha C / Logan, Catriona Y / Nusse, Roel / Pantalena-Filho, Luiz / Yang, George P / Kingsley, David M

    Bone

    2015  Volume 77, Page(s) 31–41

    Abstract: Bone morphogenetic proteins (BMPs) are key signaling molecules required for normal development of bones and other tissues. Previous studies have shown that null mutations in the mouse Bmp5 gene alter the size, shape and number of multiple bone and ... ...

    Abstract Bone morphogenetic proteins (BMPs) are key signaling molecules required for normal development of bones and other tissues. Previous studies have shown that null mutations in the mouse Bmp5 gene alter the size, shape and number of multiple bone and cartilage structures during development. Bmp5 mutations also delay healing of rib fractures in adult mutants, suggesting that the same signals used to pattern embryonic bone and cartilage are also reused during skeletal regeneration and repair. Despite intense interest in BMPs as agents for stimulating bone formation in clinical applications, little is known about the regulatory elements that control developmental or injury-induced BMP expression. To compare the DNA sequences that activate gene expression during embryonic bone formation and following acute injuries in adult animals, we assayed regions surrounding the Bmp5 gene for their ability to stimulate lacZ reporter gene expression in transgenic mice. Multiple genomic fragments, distributed across the Bmp5 locus, collectively coordinate expression in discrete anatomic domains during normal development, including in embryonic ribs. In contrast, a distinct regulatory region activated expression following rib fracture in adult animals. The same injury control region triggered gene expression in mesenchymal cells following tibia fracture, in migrating keratinocytes following dorsal skin wounding, and in regenerating epithelial cells following lung injury. The Bmp5 gene thus contains an "injury response" control region that is distinct from embryonic enhancers, and that is activated by multiple types of injury in adult animals.
    MeSH term(s) Animals ; Bone Morphogenetic Protein 5/genetics ; Fractures, Bone/genetics ; Gene Expression/genetics ; Humans ; Male ; Mice, Transgenic ; Regulatory Sequences, Nucleic Acid ; Soft Tissue Injuries/genetics
    Chemical Substances Bmp5 protein, mouse ; Bone Morphogenetic Protein 5
    Language English
    Publishing date 2015-04-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2015.04.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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