Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons
Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons
复制标题
DOI：
10.1210/en.2007-1634
复制
发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Tsai, Pei-San
中科院分区：
文献类型：
--
作者：
Chung, Wilson C. J.;Moyle, Sarah S.;Tsai, Pei-San
GnRH神经元对生殖的启动和维持至关重要。成纤维细胞生长因子受体（Fgfr 1）和Fgf 8的突变已被证明会导致卡尔曼综合征，这是一种以低促性腺激素性性腺功能减退和嗅觉丧失为特征的疾病，表明FGF信号传导对于功能性GnRH系统的形成是不可或缺的。目前尚不清楚GnRH神经元发育的哪个阶段受FGF信号传导缺陷的影响最大。GnRH神经元表达FGFR 1和FGFR 3;因此，还不清楚FGFR 1或FGFR 3是否直接促进GnRH系统发育。在这项研究中，我们研究了FGF 8，FGFR 1或FGFR 3缺陷小鼠的GnRH系统的发育，以阐明这些FGF信号成分的个体贡献。我们的研究结果表明，GnRH神经元从胚胎嗅基板的早期出现需要FGF 8信号，这是通过FGFR 1介导的，而不是FGFR 3。这些数据提供了令人信服的证据，表明发育中的GnRH系统对FGF信号传导水平的降低非常敏感。此外，Kallmann综合征源于FGF信号传导缺陷，可能主要是由于早期GnRH神经元发育缺陷，然后才迁移到前脑。
GnRH neurons are essential for the onset and maintenance of reproduction. Mutations in both fibroblast growth factor receptor (Fgfr1) and Fgf8 have been shown to cause Kallmann syndrome, a disease characterized by hypogonadotropic hypogonadism and anosmia, indicating that FGF signaling is indispensable for the formation of a functional GnRH system. Presently it is unclear which stage of GnRH neuronal development is most impacted by FGF signaling deficiency. GnRH neurons express both FGFR1 and -3; thus, it is also unclear whether FGFR1 or FGFR3 contributes directly to GnRH system development. In this study, we examined the developing GnRH system in mice deficient in FGF8, FGFR1, or FGFR3 to elucidate the individual contribution of these FGF signaling components. Our results show that the early emergence of GnRH neurons from the embryonic olfactory placode requires FGF8 signaling, which is mediated through FGFR1, not FGFR3. These data provide compelling evidence that the developing GnRH system is exquisitely sensitive to reduced levels of FGF signaling. Furthermore, Kallmann syndrome stemming from FGF signaling deficiency may be due primarily to defects in early GnRH neuronal development prior to their migration into the forebrain.