Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus.
Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus.
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DOI：
10.1007/s12035-015-9568-5
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发表时间：
2016-12
影响因子：
5.1
通讯作者：
Laezza F
中科院分区：
文献类型：
--
作者：
Alshammari MA;Alshammari TK;Nenov MN;Scala F;Laezza F
成体神经发生，即从成体哺乳动物脑中的祖细胞产生成熟神经元，与神经退行性疾病和精神疾病的病因学有关。然而，对成人神经发生基础的分子元素的透彻理解仍然是难以捉摸的。在这里，我们提供的证据，以前未描述的功能成纤维细胞生长因子14（FGF 14），脑疾病相关的因素，控制神经元的兴奋性和突触可塑性，在调节成人神经发生在齿状回（DG）。我们发现FGF 14在DG中的性别决定区Y盒2（Sox 2）阳性和双皮质素（DCX）阳性神经祖细胞的限制性亚型中动态表达。BrdU掺入研究和共聚焦成像显示，Fgf 14 −/−小鼠中Fgf 14的基因缺失导致增殖、未成熟和成熟的新生成体颗粒细胞比例发生显著变化。这导致DCX和钙视网膜蛋白（CR）阳性神经元的晚期未成熟和早期成熟群体的增加。与Fgf 14 +/+小鼠相比，电生理胞外场记录显示Fgf 14 −/−小鼠的DG输入穿孔路径的最小阈值反应降低，配对脉冲易化受损，支持突触连接中断与神经发生受损相关。这些对神经发生中FGF 14生物学的新见解揭示了与复杂脑疾病中功能中断相关的信号通路。
Adult neurogenesis, the production of mature neurons from progenitor cells in the adult mammalian brain, is linked to the etiology of neurodegenerative and psychiatric disorders. However, a thorough understanding of the molecular elements at the base of adult neurogenesis remains elusive. Here, we provide evidence for a previously undescribed function of fibroblast growth factor 14 (FGF14), a brain disease-associated factor that controls neuronal excitability and synaptic plasticity, in regulating adult neurogenesis in the dentate gyrus (DG). We found that FGF14 is dynamically expressed in restricted subtypes of Sex Determining Region Y-Box 2 (Sox2) positive and doublecortin (DCX) positive neural progenitors in the DG. BrdU incorporation studies and confocal imaging revealed that genetic deletion of Fgf14 in Fgf14−/− mice leads to a significant change in the proportion of proliferating, and immature and mature newly born adult granule cells. This results in an increase in the late immature and early mature population of DCX and calretinin (CR) positive neurons. Electrophysiological extracellular field recordings showed reduced minimal threshold response and impaired paired-pulse facilitation at the perforant path to DG inputs in Fgf14−/− compared to Fgf14+/+ mice, supporting disrupted synaptic connectivity as a correlative read-out to impaired neurogenesis. These new insights into the biology of FGF14 in neurogenesis shed light into the signaling pathways associated with disrupted functions in complex brain diseases.