Neuronal differentiation and activin signal transduction

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和II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，而不是通过抑制激活素/激活素II型受体复合体与激活素I型受体的结合来中和生物活性。FS-288对细胞表面硫酸乙酰肝素表现出较高的亲和力，而FS-315表现出较低的亲和力。目前的研究表明，细胞相关的FS-288加速了细胞对激活素的摄取，导致溶酶体酶对激活素的降解增加，从而在激活素清除系统中发挥作用。此外，在FS-288存在的情况下，活化素与非洲爪哇胚胎的动物帽子细胞孵育时，也观察到活化素通过FS-288结合到细胞表面的细胞内化和降解。在非洲爪哇胚胎发育过程中，FS-288mRNA的表达仅限于神经细胞和发育后期。这些结果表明，激活素的内吞降解必须发生在非洲爪哇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II A-N，该受体在小鼠P19胚胎癌细胞(P19细胞)的神经分化过程中被诱导表达。IIA-N基因的诱导主要与神经分化有关。II A-N在激活素受体II A膜旁区域有24个碱基的插入。在成年小鼠的脑和脊髓等神经组织中，II A-N基因只在神经组织中表达。

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.