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1997 Fiscal Year Final Research Report Summary

The Study of Molecular Basis for Congenital Molformations Using Knockout Mice

Research Project

Project/Area Number 08457221
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionNiigata University

Principal Investigator

SATOKATA Ichiro  Niigata University Medical Hospital, Lecturer, 医学部・附属病院 (70170800)

Project Period (FY) 1996 – 1997
KeywordsMsx1 / Msx2 / BMP / FGF / Shh / PTHrP / apoptosis
Research Abstract

To clarify the molecular basis for congenital malformations, we have analyzed knockout mice of the msh-class homeobox genes Msxl and Msx2 which are thought to be involved in epithelial-mesenchymal interaction during organogenesis. The developmental arrest at the bud stage in the teeth of Msxl mutants is caused by the interruption of signaling pathway between dental epithelium and mesenchyme. Msxl induced in the denal mesenchyme by BMP4 and FGF4 which are secreted from dental epithelium, in turn, induces BMP4, LEF1, and syndecan 1 in the dental mesenchyme. Msx2 mutants showed a failure of enamel formation. The reduced apoptosis in the first enamel knot of mutants seamed to be a cause of this developmental abnormality. The signaling pathway, i.e., BMP4*Msx2*BMP4*apoptosis exists and is considered to be essential for normal development of enamel organ. Msx2 mutants also manifested abnormal bone and cartilage formation. The number of osteoblasts and osteoclasts was deminished and the thick … More ness of growth plate and cortical bone was thin in the mutants. Expression of the differentiation markers for osteoblasts Cbfa1, osteonectin, Alp, osteopontin, BSP, and osteocalcin were decreased iii the developing long bone of the mutants. Expression of the differentiation markers for chondrocytes CoIII, CoIX, PTHrP, and PTH/PTHrP receptor were also reduced in the mutants. Msx2 may play an important role for the transcriptional regulation of these genes. Msx1-Msx2 double mutants manifested hypoplastic thumbs, polydactyly, syndactyly, and absence of radius and tibia. In E1O.5 double mutant limb bud, the expression of Shh in the zone of polarizing activity (ZPA) could not be deteced by in situ hybridization and Fgf4 expression was shifted from the posterior half of the apical ectodermal ridge (AER) to the anterior half. Msxl and Msx2 function upstream of Shh, and are required for the expression of Shh in the limb ZPA.Bmp4 expression in the anterior portion of the progress zone also could not be detected in double mutants. The abnormal expression of these genes is thought to cause hypoplastic thumbs, polydactyly, and absence of radius and tibia. Furthermore, Bmp4 expression was markedly reduced and inhibition of apoptosis was observed in E13.5 interdigital region of double mutants. Inhibition of apoptosis in interdigital region can cause polydactyly. Msxl and Msx2 are required for the Bmp4 expression in the anterior portion of progress zone and interdigital region, and the signal pathway, i.e., BMP and FGF from AER*Msx1 and Msx2*BMP4 in progress zone and interdigital region functions for normal limb formation. In summary, Msxl and Msx2 are thought to function as important signal mediators in the epithelial-mesenchymal interaction during organogenesis. Less

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Richard Maas: "The role of Msx genes in mammalian development" Annals of the New York Academy of Sciences. 785. 171-181 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] YiPing Chen: "Msx1 controls inductive signalling in mammalian tooth development" Development. 122. 3035-3044 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "Msx遺伝子-器官形成における上皮一間葉相互作用の誘導-" 細胞工学. 16. 668-677 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "Msx1およびMsx2" Molecular Medicine. 34. 331-333 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nisizawa K: "Screening downstream genes of a homeobox gene by differential display using knockout mouse" Acta Med.Biol.46. 63-70 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "VATER association" 診断と治療. 86. 852 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "心血管系の発生におけるMsx遺伝子の役割" 心臓. 30. 11-15 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "骨格・骨形成にかかわるホメオボックス遺伝子" 実験医学. 16. 1351-1358 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 里方一郎: "形態形成・分子メカニズム研究の最新技術" 永井教之, 250 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maas R,Chen Y,Bei M,Woo I,Satokata I.: "The role of Msx genes in mammalian development." Annals of the New York Academy of Sciences. 785. 171-181 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Chen Y,Bei M,Woo I,Satokata I,Maas R.: "Msx1 controls inductive signaling in mammalian tooth morphogenesis." Development. 122. 3035-3044 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satokata I,Uchiyama M.: "Epithelial-mesenchymal interaction regulated by Msx genes." Saibo Kogaku. 16. 668-677 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satokata I: "Uchiyama M.Msx1 and Msx2" Molecular Medicine. 34. 331-333 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishizawa K,Satokata I,Kawano Y,Uchiyama M.: "Screening downstream genes of a homeobox gene by differential display using knockout mouse." Acta Med.Biol.46. 63-70 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satokata I.: "VATER association." Sindan to Tiryo. 86 Suppl.852 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satokata I,Miyabara S,Nishizawa K,Richard Maas, Uchiyama M.: "The role of Msx genes in cardiovascular development." Sinzo. 30. 11-15 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Satokata I,Uchiyama M.: "Homeobox genes involved in skeletogenesis and bone formation." Jikken Igaku. 16. 1351-1358 (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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