Stewart Courtney E, Corella Kristina M, Samberg Brittany D, Jones Paula T, Linscott Megan L, Chung Wilson C J
School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
Brain Res. 2016 Sep 1;1646:287-296. doi: 10.1016/j.brainres.2016.06.015. Epub 2016 Jun 9.
Our previous studies showed that Fgf8 mutations 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 with Fgf8 mutations 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 in Fgf8 hypomorphic 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) how Fgf8 hypomorphy disrupts prenatal GFAP-IR midline glial cell development, and 2) whether Fgf8 hypomorphy 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-dorsal Gfap expression in midline glial cells suggesting that FGF8 function regulates midline GFAP-IR glial cell development, which when disrupted by Fgf8 deficiency 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.
我们之前的研究表明，Fgf8突变可导致卡尔曼综合征（KS），这是一种先天性低促性腺激素性性腺功能减退症，患者不会进入青春期且不育。有趣的是，一些KS患者还存在胼胝体发育不全（ACC），这表明KS的病理变化并不局限于生殖功能。在此，我们探究FGF8功能障碍是否是部分KS患者ACC的潜在病因。的确，早期对Fgf8突变转基因小鼠的研究报告称存在胼胝体形成失败或不完全的情况。对转基因小鼠的进一步研究表明，FGF8功能很可能能防止产前清除海马灰层（IG）和中线拉链（MZ）中胶质纤维酸性蛋白（GFAP）免疫反应性（IR）胶质细胞，这两个是胼胝体形成所需的前背侧中线区域（即在胚胎第15.5 - 18.5天之间）。在此，我们检验了FGF8功能对GFAP - IR中线胶质细胞存活至关重要这一假设。首先，我们测量了Fgf8低表达小鼠在胚胎胼胝体形成过程中前背侧中线区域的细胞凋亡发生率。其次，我们对产前和产后发育期间前背侧中脑区域的GFAP表达进行了定量，以便研究：1）Fgf8低表达如何破坏产前GFAP - IR中线胶质细胞发育，以及2）Fgf8低表达是否会持续破坏产后GFAP - IR中线胶质细胞发育。我们的结果表明，围产期FGF8信号传导对于中线胶质细胞中前背侧Gfap表达开始的时间很重要这表明FGF8功能调节中线GFAP - IR胶质细胞发育，当这种发育因Fgf8缺乏而受到破坏时会阻止胼胝体的形成。这些研究为FGF信号传导缺陷的KS患者胼胝体形成可能失败提供了基于实验的机制解释。
