Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system.
Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system.
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多个成纤维细胞生长因子信号传导成分中的复合缺陷会差异影响鼠促性腺营养蛋白释放激素系统。
DOI：
10.1111/j.1365-2826.2010.02024.x
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发表时间：
2010-08
影响因子：
3.2
通讯作者：
Tsai PS
中科院分区：
文献类型：
--
作者：
Chung WC;Matthews TA;Tata BK;Tsai PS
促性腺激素释放激素（GnRH）神经元控制生育的发生和维持。GnRH系统的异常发育是卡尔曼综合征不孕的基础[KS;特发性低促性腺激素性性腺功能减退症（IHH）和嗅觉丧失]。一些KS患者在成纤维细胞生长因子受体1（Fgfr 1）和Fgf 8基因中存在突变。这两个基因在GnRH神经元发育中的生物学意义得到了以下观察结果的证实，即GnRH神经元在任何一个基因缺陷的新生转基因小鼠中严重减少。在本研究中，我们假设Fgf 8及其同源受体Fgfr 1和Fgfr 3的复合缺陷可能导致对GnRH系统的更有害的影响，从而导致携带这些突变的患者的更严重的生殖表型。通过对Fgfr 1/Fgf 8、Fgfr 3/Fgf 8或Fgfr 1/Fgfr 3双基因杂合突变的成年转基因小鼠中GnRH神经元的数量进行计数来检验这一假设。Fgfr 1、Fgf 8或Fgfr 3的单基因杂合突变导致GnRH神经元总数减少30-50%。有趣的是，Fgfr 1/Fgf 8双基因突变的小鼠与Fgfr 1或Fgf 8单独杂合缺陷的小鼠相比，GnRH神经元的减少更大。在Fgfr 3/Fgf 8或Fgfr 1/Fgfr 3双基因杂合突变的小鼠中未检测到这种复合效应。这些结果支持以下假设：与Fgfr 1或Fgf 8单基因单倍体突变患者相比，Fgfr 1/Fgf 8双基因突变的IHH/KS患者的GnRH神经元群体可能进一步减少。因为只有Fgfr 1/Fgf 8化合物缺乏导致更大的GnRH系统缺陷，这也表明这些成纤维细胞生长因子信号传导组分以高度特异性的方式相互作用，以支持GnRH神经元发育。
Gonadotrophin-releasing hormone (GnRH) neurones control the onset and maintenance of fertility. Aberrant development of the GnRH system underlies infertility in Kallmann syndrome [KS; idiopathic hypogonadotropic hypogonadism (IHH) and anosmia]. Some KS patients harbour mutations in the fibroblast growth factor receptor 1 (Fgfr1) and Fgf8 genes. The biological significance of these two genes in GnRH neuronal development was corroborated by the observation that GnRH neurones were severely reduced in newborn transgenic mice deficient in either gene. In the present study, we hypothesised that the compound deficiency of Fgf8 and its cognate receptors, Fgfr1 and Fgfr3, may lead to more deleterious effects on the GnRH system, thereby resulting in a more severe reproductive phenotype in patients harbouring these mutations. This hypothesis was tested by counting the number of GnRH neurones in adult transgenic mice with digenic heterozygous mutations in Fgfr1/Fgf8, Fgfr3/Fgf8 or Fgfr1/Fgfr3. Monogenic heterozygous mutations in Fgfr1, Fgf8 or Fgfr3 caused a 30–50% decrease in the total number of GnRH neurones. Interestingly, mice with digenic mutations in Fgfr1/Fgf8 showed a greater decrease in GnRH neurones compared to mice with a heterozygous defect in the Fgfr1 or Fgf8 alone. This compounding effect was not detected in mice with digenic heterozygous mutations in Fgfr3/Fgf8 or Fgfr1/Fgfr3. These results support the hypothesis that IHH/KS patients with digenic mutations in Fgfr1/Fgf8 may have a further reduction in the GnRH neuronal population compared to patients harbouring monogenic haploid mutations in Fgfr1 or Fgf8. Because only Fgfr1/Fgf8 compound deficiency leads to greater GnRH system defect, this also suggests that these fibroblast growth factor signalling components interact in a highly specific fashion to support GnRH neuronal development.
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影响因子：
30.8
作者：
Dodé, C;Levilliers, J;Hardelin, JP
通讯作者：
Hardelin, JP
影响因子：
4.8
作者：
SAMSON, WK;MCCANN, SM
通讯作者：
MCCANN, SM
影响因子：
64.8
作者：
FRANCO, B;GUIOLI, S;BALLABIO, A
通讯作者：
BALLABIO, A
影响因子：
4.8
作者：
Chung, Wilson C. J.;Moyle, Sarah S.;Tsai, Pei-San
通讯作者：
Tsai, Pei-San
影响因子：
4.5
作者：
Dode, Catherine;Teixeira, Luis;Levilliers, Jacqueline;Fouveaut, Corinne;Bouchard, Philippe;Kottler, Marie-Laure;Lespinasse, James;Lienhardt-Roussie, Anne;Mathieu, Michele;Moerman, Alexandre;Morgan, Graeme;Murat, Arnaud;Toublanc, Jean-Edmont;Wolczynski, Slawomir;Delpech, Marc;Petit, Christine;Young, Jacques;Hardelin, Jean-Pierre
通讯作者：
Hardelin, Jean-Pierre