Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction linked to the Fragile X messenger ribonucleoprotein (Fmr1) gene mutation.
Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction linked to the Fragile X messenger ribonucleoprotein (Fmr1) gene mutation.
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DOI：
10.3389/fendo.2023.1129534
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
脆性X信使核糖核蛋白1（FMR 1）基因突变导致脆性X综合征，这是智力残疾最常见的单基因原因。FMR 1的突变也与生殖障碍有关，例如女性生殖功能的早期停止。虽然在了解精神障碍的机制方面取得了进展，但生殖障碍的原因尚不清楚。FMR 1相关的生殖疾病仅从内分泌角度进行了研究，而FMR 1在控制生殖的神经元中的作用没有得到解决。在这里，我们证明了类似于FMR1突变的女性，女性Fmr1 null小鼠早期停止繁殖。然而，年轻的无效雌性显示更大的窝，卵巢中的黄体更多，循环中的雌二醇、孕酮、睾酮和促性腺激素增加。卵巢切除术揭示了下丘脑和卵巢对促性腺激素升高的作用。下丘脑中几种突触分子的mRNA和蛋白质水平的改变被鉴定，表明下丘脑调节异常的原因。黄体血管化增加，Fmr1无效卵巢中生长卵泡的交感神经支配增加，GnRH神经元中突触GABAA受体数量增加（对GnRH神经元具有兴奋性）分别导致FSH和LH增加。未修饰和卵巢切除的Fmr1空细胞LH脉冲频率增加，表明Fmr1空细胞表现出过度活跃的GnRH神经元，无论卵巢反馈。这些结果揭示了Fmr1在调节GnRH神经元分泌中的功能，并指出GnRH神经元除了卵巢神经支配外，在Fmr1介导的生殖障碍的病因学中的作用。
Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene cause Fragile X Syndrome, the most common monogenic cause of intellectual disability. Mutations of FMR1 are also associated with reproductive disorders, such as early cessation of reproductive function in females. While progress has been made in understanding the mechanisms of mental impairment, the causes of reproductive disorders are not clear. FMR1-associated reproductive disorders were studied exclusively from the endocrine perspective, while the FMR1 role in neurons that control reproduction was not addressed. Here, we demonstrate that similar to women with FMR1 mutations, female Fmr1 null mice stop reproducing early. However, young null females display larger litters, more corpora lutea in the ovaries, increased inhibin, progesterone, testosterone, and gonadotropin hormones in the circulation. Ovariectomy reveals both hypothalamic and ovarian contribution to elevated gonadotropins. Altered mRNA and protein levels of several synaptic molecules in the hypothalamus are identified, indicating reasons for hypothalamic dysregulation. Increased vascularization of corpora lutea, higher sympathetic innervation of growing follicles in the ovaries of Fmr1 nulls, and higher numbers of synaptic GABAA receptors in GnRH neurons, which are excitatory for GnRH neurons, contribute to increased FSH and LH, respectively. Unmodified and ovariectomized Fmr1 nulls have increased LH pulse frequency, suggesting that Fmr1 nulls exhibit hyperactive GnRH neurons, regardless of the ovarian feedback. These results reveal Fmr1 function in the regulation of GnRH neuron secretion, and point to the role of GnRH neurons, in addition to the ovarian innervation, in the etiology of Fmr1-mediated reproductive disorders.
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影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
3.5
作者：
Macpherson JN;Murray A
通讯作者：
Murray A
影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
4.9
作者：
Berman RF;Buijsen RA;Usdin K;Pintado E;Kooy F;Pretto D;Pessah IN;Nelson DL;Zalewski Z;Charlet-Bergeurand N;Willemsen R;Hukema RK
通讯作者：
Hukema RK
影响因子：
2.5
作者：
Darnell, JC;Mostovetsky, O;Darnell, RB
通讯作者：
Darnell, RB