ACTIONS OF INSULIN-LIKE GROWTH FACTOR-1 ON BRAIN DEVELOPMENT

胰岛素样生长因子-1 对大脑发育的作用

• 批准号: 06680769
• 负责人: NOGUCHI Tetsuya
• 金额: $ 1.47万
• 依托单位: TOHO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06680769/
• 关键词: Brain development; Endocrine mutant mouse; Growth hormone (GH); Hypomyelination; Insulin-like growth factor-1 (IGF-1); IGF binding proteins; IGF-1 receptor; Pygmy mouse (pg); 成長ホルモン; Insulin-like-growth factor-1 (IGF-1); pgマウス; 甲状腺ホルモン; IGF-1

To understand the mechanism of insulin-like growth factor-1 (IGF-1), as a secondary hormone of growth hormone, on brain development, we examined the central nervous system of the hormone-deficient Snell pituitary dwarf (dw), Little (lit), hypothyroid (hyt), congenital goiter (cog), and Pygmy (pg) mutant mice, which were showed hypomyelination in the cerebrum at the 40th day of age. Our findings are as follows : (1) there were no differences of IGF-1 concentration in the three parts of brain (cerebrum, brain stem, and cerebellum) between the 5 mutants and the normal control mice. Serum IGF-1 levels and IGF-1 concentraitons of liver and kidney in the dw, lit, hyt and cog mutant mice were found to be significantly lower than in the controls. These differences in IGF-1 concentration were not observed in the pg mouse. These results indicated that serum IGF-1 production is induced by thyroid hormones as well as by GH.(2) The serum IGF binding protein (IGFBP) -3 and IGFBP-4 levels were signif … More icantly reduced in dw, lit, hyt and cog mutant mice. IGFBP-2 levels were also reduced in the lit, hyt and cog mice, although that of the dw serum was found to be greatly elevated. No differences in the serum IGFBPs were found in the pg mouse. Consequently, the ration of IGFBP-3% : IGFBP-2% (the percentage of IGFBP-3 fraction of total IGFBP (IGFBP-3%) divided by that of IGFBP-2 (IGFBP-2%)) was decreased in GH-deficient mice but increased in hypothyroid mice, suggesting that IGFBP-3 and IGFBP-2 production in the liver is induced by GH and thyroid hormones respectively. (3) Serum IGF-1 level in the 20 day-old pg mouse was found to significantly decrease to 61% of the normal control. The liver and kidney IGF-1 levels in the 20 day-old pg mouse were also found to be lower than in the normal controls, 69% and 76% of the normal controls, respectively. The cerebrum and brain stem IGF-1 levels in the 20 day-old pg mouse were also found to be lower than in the normal controls, 89% and 65% of the normal controls, respectively. But no differences in IGF-1 level were found in the 20 day-old pg mouse cerebellum. These findings suggest that IGF-1 might have an indispensable role on neural development during the first 20 days of postnatal life. (4) There were no differences on both affinity cross-linking ^<125>I-labeled IGF-1 to microsomes prepared from the three parts of brain and phosphorylations of the beta subunits of the IGF-1 receptora in the three parts of brain between 40 day-old pg mouse and the normal control mouse. These results indicated that the pg mouse might have abnormalities on syntheses of IGF-1, IGFBPs and IGF-1 receptors at the prenatal and neonatal stage, and/or interactions between them on brain. Less

为了了解胰岛素样生长因子-1 （IGF-1）作为生长激素的次级激素对大脑发育的影响机制，我们检测了激素缺乏的Snell垂体矮子（dw）、Little （lit）、甲状腺功能减退（hyt）、先天性甲状腺肿（cog）和侏儒（pg）突变小鼠的中枢神经系统，这些小鼠在40日龄时大脑出现了髓鞘发育低下。我们的研究结果如下：(1)5个突变体小鼠大脑3个部位（大脑、脑干和小脑）的IGF-1浓度与正常对照小鼠没有差异。dw、lit、hyt和cog突变小鼠血清IGF-1水平和肝脏、肾脏IGF-1浓度均显著低于对照组。在pg小鼠中没有观察到IGF-1浓度的这些差异。这些结果表明血清IGF-1的产生是由甲状腺激素和生长激素诱导的。(2) dw、lit、hyt和cog突变小鼠血清IGF结合蛋白(IGFBP) -3和IGFBP-4水平明显降低。IGFBP-2水平在lit， hyt和cog小鼠中也有所降低，尽管dw血清中的IGFBP-2水平被发现大大升高。pg小鼠血清igfbp未见差异。因此，IGFBP-3%: IGFBP-2% (IGFBP-3占总IGFBP的百分比（IGFBP-3%）除以IGFBP-2 （IGFBP-2%）的比例在GH缺乏小鼠中降低，而在甲状腺功能减退小鼠中升高，提示肝脏中IGFBP-3和IGFBP-2的产生分别是由GH和甲状腺激素诱导的。(3) 20日龄pg小鼠血清IGF-1水平显著降低，为正常对照的61%。20日龄pg小鼠的肝脏和肾脏IGF-1水平也低于正常对照组，分别为正常对照组的69%和76%。20日龄pg小鼠的大脑和脑干IGF-1水平也低于正常对照组，分别为正常对照组的89%和65%。但在20日龄的pg小鼠小脑中没有发现IGF-1水平的差异。这些发现表明，IGF-1可能在出生后20天的神经发育中起着不可或缺的作用。(4) 40日龄pg小鼠与正常对照小鼠在脑三部位制备的IGF-1亲和交联和脑三部位IGF-1受体β亚基磷酸化方面均无差异。这些结果提示pg小鼠在产前和新生儿阶段可能存在IGF-1、igfbp和IGF-1受体合成异常，以及/或它们之间在脑内的相互作用异常。少

项目成果

Noguchi, T.: "Effects of growth hormone on cerebral development:Morphological studies" Horm Res. 45. 5-17 (1996)

野口，T.：“生长激素对大脑发育的影响：形态学研究”Horm Res。

Sugisaki,T.,et al.: "The influence of endocrine factors on the serum concentrations of insulin-like growth factor-I(IGF-I)and IGF-binding proteins." J.Endocrinol. 138. 467-477 (1993)

Sugisaki,T.,et al.：“内分泌因素对胰岛素样生长因子-I (IGF-I) 和 IGF 结合蛋白血清浓度的影响。”

Noguchi T: "Effects of growth hormone on cerebral development : Morpological studies" Horm Res. 45. 5-17 (1996)

野口 T：“生长激素对大脑发育的影响：形态学研究”Horm Res。

Sugisaki T: "The influence of endocrine factors on the serum concentrations of insulin-like growth factor-I (IGF-1) and IGF-binding proteins" J Endocrinol. 138. 467-477 (1993)

Sugisaki T：“内分泌因素对胰岛素样生长因子-I (IGF-1) 和 IGF 结合蛋白血清浓度的影响”J Endocrinol。

Sugisaki T,Yamada T,Takamatsu K,Noguchi T: "The influence of endocrine factors on the serum concentrations of insulin-like growth factor-I (IGF-I) and IGF-binding proteins." J Endocrinol. 138. 467-477 (1993)

Sugisaki T、Yamada T、Takamatsu K、Noguchi T：“内分泌因素对胰岛素样生长因子-I (IGF-I) 和 IGF 结合蛋白血清浓度的影响。”