Analysis of an inner nuclear membrane protein as a novel signaling regulator

• Project/Area Number: 16570152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Akita University
• Principal Investigator: OSADA Shin-Ichi Akita University, Graduate School of Medicine, COE Research Leader, 大学院・医学研究科, COE主任研究員 (00244484)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,700,000 (Direct Cost: ¥3,700,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Angiogenesis / Nuclear Membrane Protein / Signal Transduction / TGF-β / Developmental Biology / Knock-out Mouse / International Collaboration / United States of America / 血管形成 / ジーントラップマウス / 発生 / 国際情報交換(アメリカ合衆国)

Research Abstract

A growing number of integral inner nuclear membrane (INM) proteins have been implicated in diverse cellular functions. Man1, an INM protein, has recently been shown to regulate transforming growth factor (TGF)-β signaling by interacting with receptor-associated Smads. However, the in vivo roles of Man1 have not been fully characterized. To obtain insights into the requirement for man1 in mammalian development and cellular functions, we generated Man1-deficient mice lacking the Smad interacting domain with an embryonic stem cell line in which man1 had been disrupted by gene trapping. Man1 heterozygous mice were normal and fertile. In contrast, man1 homozygouse (Man1^<-/->) embryos die at midgestation because of defects in embryonic vasculature ; the primary capillary plexus forms, but subsequent remodeling is perturbed. It has been proposed that the angiogenesis process is divided into two phases, the activation and resolution/maturation phases, both of which are regulated by TGF-β1. We have demonstrated, in Man1^<-/-> embryos, the expression of TGF-β1 is up-regulated and Smad2/3 signaling is abnormally activated, resulting in increased extracellular matrix deposition, a hallmark of the resolution phase of angiogenesis. These results have revealed an unexpected role of Man1 in angiogenesis and provide the first evidence that vascular remodeling can be regulated at the INM through the interaction between man1 and Smads.

Research Products

• [Journal Article] Systemic screening for genes specifically expressed in the anterior neuroectoderm during early Xenopus development (2005)
  • Author(s): Takahashi, N.
  • Journal Title: Int. J. Dev. Biol 49 Pages: 939-951
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Systemic screening for genes specifically expressed in the anterior neuroectoderm during early Xenopus development (2005)
  • Author(s): Takahashi, N., Tochimoto, N., Ohmori, S., Itoh, M., Inamori, M., Mamada, H., Shinga, J., Osada, S-I., Taira, M.
  • Journal Title: Int.J.Dev.Biol. 49 Pages: 939-951
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Systemic screening for genes specifically expressed in the anterior neuroectoderm during early Xenopus development (2005)
  • Author(s): Takahashi, N.
  • Journal Title: Int.J.Dev.Biol 49 Pages: 939-951