Perinatal midline astrocyte development is impaired in fibroblast growth factor 8 hypomorphic mice.
Perinatal midline astrocyte development is impaired in fibroblast growth factor 8 hypomorphic mice.
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成纤维细胞生长因子 8 低效型小鼠的围产期中线星形胶质细胞发育受损。
DOI：
10.1016/j.brainres.2016.06.015
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发表时间：
2016
期刊：
影响因子：
2.9
通讯作者：
Chung,WilsonCJ
中科院分区：
文献类型：
--
作者：
Stewart,CourtneyE;Corella,KristinaM;Samberg,BrittanyD;Jones,PaulaT;Linscott,MeganL;Chung,WilsonCJ
我们先前的研究表明，Fgf8突变可导致Kallmann综合征(KS)，这是一种先天性低促性腺激素减退症，患者不经历青春期并不育。有趣的是，一些KS患者也有胼胝体发育不全(ACC)，这表明KS的病理并不局限于生殖功能。在这里，我们询问FGF8功能障碍是否是一些KS患者ACC的潜在原因。事实上，在带有Fgf8突变的转基因小鼠中的早期研究报告说，存在不成功或不完整的胼胝体形成。在转基因小鼠中的其他研究表明，FGF8的功能很可能阻止灰腹大鼠(IG)和中线拉链(MZ)中的胶质纤维酸性蛋白(GFAP)免疫反应(IR)胶质细胞的出生前消除，这两个前背部中线区域是穹隆形成所必需的(即，在胚胎天数(E)15.5-18.5之间)。在这里，我们验证了FGF8功能对GFAP-IR中线神经胶质细胞的生存至关重要的假设。首先，我们测量了Fgf8基因缺陷小鼠在胚胎胼胝体形成过程中前背部中线区域细胞凋亡的发生率。其次，我们对出生前和出生后中脑前背侧区GFAP的表达进行了定量研究，以研究：1)Fgf8亚型如何扰乱出生前GFAP-IR中线胶质细胞的发育；2)Fgf8亚型是否继续扰乱出生后GFAP-IR中线胶质细胞的发育。我们的结果表明，围产期的FGF8信号对中线胶质细胞的前背Gfap1表达的开始时间是重要的，这表明FGF8功能调节中线GFAP-IR胶质细胞的发育，当FGF8缺乏时，该信号通路阻止了结缔组织的形成。这些研究提供了一种基于实验的机制解释，解释了为什么成纤维细胞生长因子信号缺陷的KS患者的胼胝体形成可能失败。
Our previous studies showed thatFgf8mutations can cause Kallmann syndrome (KS), a form of congenital hypogonadotropic hypogonadism, in which patients do not undergo puberty and are infertile. Interestingly, some KS patients also have agenesis of the corpus callosum (ACC) suggesting that KS pathology is not limited to reproductive function. Here, we asked whether FGF8 dysfunction is the underlying cause of ACC in some KS patients. Indeed, early studies in transgenic mice withFgf8mutations reported the presence of failed or incomplete corpus callosum formation. Additional studies in transgenic mice showed that FGF8 function most likely prevents the prenatal elimination of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) glial cells in the indusium griseum (IG) and midline zipper (MZ), two anterior-dorsal midline regions required for corpus callosum formation (i.e., between embryonic days (E) 15.5–18.5). Here, we tested the hypothesis that FGF8 function is critical for the survival of the GFAP-IR midline glial cells. First, we measured the incidence of apoptosis in the anterior-dorsal midline region inFgf8hypomorphic mice during embryonic corpus callosum formation. Second, we quantified the GFAP expression in the anterior-dorsal midbrain region during pre- and postnatal development, in order to study: 1) howFgf8hypomorphy disrupts prenatal GFAP-IR midline glial cell development, and 2) whetherFgf8hypomorphy continues to disrupt postnatal GFAP-IR midline glial cell development. Our results indicate that perinatal FGF8 signaling is important for the timing of the onset of anterior-dorsalGfapexpression in midline glial cells suggesting that FGF8 function regulates midline GFAP-IR glial cell development, which when disrupted byFgf8deficiency prevents the formation of the corpus callosum. These studies provide an experimentally-based mechanistic explanation as to why corpus callosum formation may fail in KS patients with deficits in FGF signaling.