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

为了解胰岛素样生长因子-1(IGF-1)作为生长激素的次要激素在脑发育中的作用机制，我们对40d龄出现脑髓鞘减退的激素缺乏性Snell垂体性侏儒(DW)、小(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进行了观察。我们的研究结果如下：(1)5个突变体小鼠大脑三个部位(大脑、脑干和小脑)的IGF-1浓度与正常对照小鼠无差异。DW、LIT、HYT和COG突变小鼠的血清IGF-1水平和肝、肾组织中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。…患者血清IGFBP-3和IGFBP-4水平显著高于正常对照组。在dw、litt、hyt和cog突变小鼠中的减少更为明显。LIT、HYT和COG小鼠的IGFBP-2水平也降低，尽管dw血清的IGFBP-2水平显著升高。PG组小鼠血清IGFBPs无明显差异。因此，在GH缺陷小鼠，IGFBP-3：IGFBP-2(IGFBP-3占总IGFBP的百分比(IGFBP-3%)除以IGFBP-2的百分比(IGFBP-2%))的比例降低，而在甲状腺功能低下的小鼠则增加，这表明肝脏中IGFBP-3和IGFBP-2的产生分别由GH和甲状腺激素诱导。(3)20日龄PG小鼠血清IGF-1水平显著下降，为正常对照组的61%。20日龄PG小鼠肝脏和肾脏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1%和65%。而20日龄PG小鼠小脑中IGF-1水平无明显差异。这些发现表明，在出生后的头20天，IGF-1可能在神经发育中起着不可或缺的作用。(4)40日龄PG小鼠与正常对照组小鼠脑内IGF-1受体β亚基的亲和交联率和IGF-1受体β亚基的磷酸化水平无明显差异。这些结果表明，PG小鼠在产前和新生儿期可能存在IGF-1、IGFBPs和IGF-1受体的合成异常，和/或它们在脑内的相互作用。较少

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