Neuronal differentiation and activin signal transduction

神经元分化和激活素信号转导

• 批准号: 08044298
• 负责人: SUGINO Hiromu
• 金额: $ 1.54万
• 依托单位: The Institute for Enzyme Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044298/
• 关键词: Activin; Follistatin; Activin receptor; Neural induction; Heparan sulfate; Mesoderm induction; Central nerve system

The present study was conducted to understand a role of follistatin (FS), an activin-binding protein, in neural induction.The interaction between activin type I and type II receptors is necessary for activin signal transduction. We found that FS can neutralize bioactivity by interference with binding of activin to all known activin type II receptors, rather than that FS inhibits the binding of the type I receptor to the activin/activin type II receptor complex.There are two types of FS : FS-288 and FS-315. FS-288 exhibits high affinity for cell surface heparan sulfate, whereas FS-315 shows low affinity. The present study demonstrated that cell-associated FS-288 accelerates the uptake of activin into cells, leading to increased degradation by lysosomal enzymes, and thus plays a role in the activin clearance system. Furthermore, the cellular internalization and degradation of activin via FS-288 bound to cell surface was also observed when in the presence of FS-288, activin was incubated with animal cap cells from Xenopus embryos. Expression of FS-288 mRNA in developing Xenopus embryos was restricted to the neurula and later stages. These results suggest that the endocytotic degradation of activin must occur at an early stage of neural differntiation in Xenopus embryos to remove the activin signal from cell surfaces.We identified a novel type II activin receptor, II A-N,the expression of which was induced during the neural differentiation of mouse P19 embryonal carcinoma cells (P19 cells). The induction of II A-N mRNA occurred predominantly in conjunction with neural differentiation. II A-N was found to have a 24 bp insertion in the juxtamembrane region of the activin receptor type II A.In vivo expression of II A-N mRNA was detected only in the neural tissues such as brain and spinal cord in adult mouse.

本研究旨在了解激活素结合蛋白卵泡抑素（FS）在神经诱导中的作用，激活素I型和II型受体之间的相互作用是激活素信号转导所必需的。我们发现FS可以通过干扰激活素与所有已知的激活素II型受体的结合来中和生物活性，而不是FS抑制I型受体与激活素/激活素II型受体复合物的结合。FS-288对细胞表面硫酸乙酰肝素表现出高亲和力，而FS-315表现出低亲和力。本研究表明，细胞相关的FS-288加速激活素进入细胞的摄取，导致溶酶体酶降解增加，因此在激活素清除系统中发挥作用。此外，当在FS-288的存在下，将激活素与来自爪蟾胚胎的动物帽细胞孵育时，还观察到激活素通过与细胞表面结合的FS-288的细胞内化和降解。FS-288 mRNA在非洲爪蟾胚胎发育中的表达仅限于神经胚和后期阶段。这些结果表明，激活素的内吞降解必须发生在非洲爪蟾胚胎神经分化的早期阶段，以消除细胞表面的激活素信号，我们发现了一种新的II型激活素受体，IIA-N，它的表达在小鼠P19胚胎癌细胞（P19细胞）神经分化过程中被诱导。II A-N mRNA的诱导主要发生在与神经分化。结果表明，在激活素Ⅱ A型受体的胞膜区有一个24 bp的插入片段，在成年小鼠的脑、脊髓等神经组织中有表达。

项目成果

Osamu Hashimoto: "A Novel Role of Follistatin, an Activin-Binding Protein, in the Inhibition of Activin Action in Rat Pituitary Cells" J.Biol.Chem.in press. (1997)

Osamu Hashimoto：“卵泡抑素（一种激活素结合蛋白）在抑制大鼠垂体细胞激活素作用中的新作用”J.Biol.Chem.in 出版社。

Osamu Hashimoto: "A Novel Role of Follistatin, an Activin-Binding Protein, in the Inhibition of Activin Action in Rat Pituitary Cells" J.Biol.Chem.(in press). (1997)

Osamu Hashimoto：“卵泡抑素（一种激活素结合蛋白）在抑制大鼠垂体细胞激活素作用中的新作用”J.Biol.Chem.（出版中）。

Johan P.de Winter: "Follistatins Neutralize Activin Bioactivity by Inhibition of Activin Binding to Its Type II Receptors" Molec.Cell.Endocrinol.116. 105-114 (1996)

Johan P.de Winter：“卵泡抑素通过抑制激活素与其 II 型受体结合来中和激活素生物活性”Molec.Cell.Endocrinol.116。