Adult-Specific Systemic Over-Expression Reveals Novel In Vivo Effects of the Soluble Forms of ActRIIA, ActRIIB and BMPRII

Kengo Yamawaki, Shinobu Ueda, Tsutomu Okada, Takeshi Oshima, Makoto Kakitani, Takashi Kato, Kazuma Tomizuka

    研究成果: Article

    7 引用 (Scopus)

    抄録

    Bone morphogenetic proteins (BMPs)/growth differentiation factors (GDFs), which belong to the TGF-beta superfamily, are pleiotropic factors that play a role in regulating the embryonic development and postnatal homeostasis of various organs and tissues by controlling cellular differentiation, proliferation and apoptosis. Conventional transgenic and knockout (KO) mouse approaches have provided only limited information regarding the in vivo functions of BMP signaling in adult animals due to the effects on prenatal development and the difficulty in manipulating multiligand signals simultaneously. We recently produced transgenic chimeric mice(Tg chimeras) in which the soluble IgG1-Fc fusion protein of three BMP type II receptors (ActRIIA, ActRIIB, BMPRII) was highly circulated (281-709 μg/ml), specifically in adult mouse blood. Since each BMP receptor can bind to multiple BMP ligands, these Tg chimeras should be useful to investigate the effects of trapping multiple BMP ligands. Remarkably, some phenotypes were unexpected based on previous studies, such as KO mouse analyses, presumably representing the effects of the multiple ligand trapping. These phenotypes included increased red blood cells (RBCs) and decreased viability in adults. In a further study, we focused on the phenotype of increased RBCs and found that extramedullary hematopoiesis in the spleen, not in the bone marrow, was increased using histological and flow cytometric analyses. Although it remains to be elucidated whether the transgene products affect the tissues directly or indirectly, our data provide novel and important insight into the biological functions of the soluble IgG1-Fc fusion protein of three BMP type II receptors in adults, and our approach should have broad applications to research on other ligand receptor families and studies involving mouse models.

    元の言語English
    記事番号e78076
    ジャーナルPLoS One
    8
    発行部数10
    DOI
    出版物ステータスPublished - 2013 10 21

    Fingerprint

    bone morphogenetic proteins
    Bone Morphogenetic Proteins
    Type II Bone Morphogenetic Protein Receptors
    Ligands
    Blood
    Phenotype
    Knockout Mice
    Transgenic Mice
    Fusion reactions
    Immunoglobulin G
    Erythrocytes
    Bone Morphogenetic Protein Receptors
    Growth Differentiation Factors
    Extramedullary Hematopoiesis
    receptors
    Tissue
    chimerism
    mice
    phenotype
    trapping

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    これを引用

    Adult-Specific Systemic Over-Expression Reveals Novel In Vivo Effects of the Soluble Forms of ActRIIA, ActRIIB and BMPRII. / Yamawaki, Kengo; Ueda, Shinobu; Okada, Tsutomu; Oshima, Takeshi; Kakitani, Makoto; Kato, Takashi; Tomizuka, Kazuma.

    :: PLoS One, 巻 8, 番号 10, e78076, 21.10.2013.

    研究成果: Article

    Yamawaki, Kengo ; Ueda, Shinobu ; Okada, Tsutomu ; Oshima, Takeshi ; Kakitani, Makoto ; Kato, Takashi ; Tomizuka, Kazuma. / Adult-Specific Systemic Over-Expression Reveals Novel In Vivo Effects of the Soluble Forms of ActRIIA, ActRIIB and BMPRII. :: PLoS One. 2013 ; 巻 8, 番号 10.
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    abstract = "Bone morphogenetic proteins (BMPs)/growth differentiation factors (GDFs), which belong to the TGF-beta superfamily, are pleiotropic factors that play a role in regulating the embryonic development and postnatal homeostasis of various organs and tissues by controlling cellular differentiation, proliferation and apoptosis. Conventional transgenic and knockout (KO) mouse approaches have provided only limited information regarding the in vivo functions of BMP signaling in adult animals due to the effects on prenatal development and the difficulty in manipulating multiligand signals simultaneously. We recently produced transgenic chimeric mice(Tg chimeras) in which the soluble IgG1-Fc fusion protein of three BMP type II receptors (ActRIIA, ActRIIB, BMPRII) was highly circulated (281-709 μg/ml), specifically in adult mouse blood. Since each BMP receptor can bind to multiple BMP ligands, these Tg chimeras should be useful to investigate the effects of trapping multiple BMP ligands. Remarkably, some phenotypes were unexpected based on previous studies, such as KO mouse analyses, presumably representing the effects of the multiple ligand trapping. These phenotypes included increased red blood cells (RBCs) and decreased viability in adults. In a further study, we focused on the phenotype of increased RBCs and found that extramedullary hematopoiesis in the spleen, not in the bone marrow, was increased using histological and flow cytometric analyses. Although it remains to be elucidated whether the transgene products affect the tissues directly or indirectly, our data provide novel and important insight into the biological functions of the soluble IgG1-Fc fusion protein of three BMP type II receptors in adults, and our approach should have broad applications to research on other ligand receptor families and studies involving mouse models.",
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    AU - Okada, Tsutomu

    AU - Oshima, Takeshi

    AU - Kakitani, Makoto

    AU - Kato, Takashi

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