The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation.
The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation.
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DOI：
10.1371/journal.pone.0074967
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Friedmann T
中科院分区：
文献类型：
--
作者：
Kang TH;Park Y;Bader JS;Friedmann T
嘌呤能管家基因次黄嘌呤鸟嘌呤磷酸核糖转移酶 (HPRT) 突变导致严重神经发育性 Lesch Nyhan 病 (LND) 的机制尚不清楚。 HPRT 缺陷最常见的神经后果是神经递质多巴胺 (DA) 的基底神经节表达缺陷和 DA 神经元功能异常。我们已经报道，HPRT 缺陷导致多种 DA 相关发育功能的表达失调以及多种 HPRT 缺陷细胞（包括人诱导多能干细胞）中的细胞信号传导缺陷。我们现在描述了 HPRT 缺陷的小鼠 ESD3 胚胎干细胞神经元分化过程中基因表达研究的结果，并报告 HPRT 敲低导致从神经元基因表达显着转变为神经胶质细胞基因表达，并失调 Sox2 及其调节因子的表达，这些基因对干细胞多能性和神经元/胶质细胞命运决定至关重要。此外，HPRT 缺乏会导致许多细胞功能失调，包括控制细胞周期和增殖机制、RNA 代谢、DNA 复制和修复、复制应激、溶酶体功能、膜运输、血小板激活信号通路 (SPPA) 多个神经传递系统以及鞘脂、硫和聚糖代谢。我们认为 HPRT 缺陷的神经畸变是由这些多系统代谢错误的组合效应造成的。由于其中一些畸变也存在于阿尔茨海默病和亨廷顿病中，我们预测其中一些系统缺陷在不同的神经发育和神经退行性疾病中共同发挥相似的神经病理作用，因此可能为阐明发病机制和设计发育和遗传疾病的新潜在治疗靶点提供新的实验机会。
The mechanisms by which mutations of the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) cause the severe neurodevelopmental Lesch Nyhan Disease (LND) are poorly understood. The best recognized neural consequences of HPRT deficiency are defective basal ganglia expression of the neurotransmitter dopamine (DA) and aberrant DA neuronal function. We have reported that HPRT deficiency leads to dysregulated expression of multiple DA-related developmental functions and cellular signaling defects in a variety of HPRT-deficient cells, including human induced pluripotent stem (iPS) cells. We now describe results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells and report that HPRT knockdown causes a marked switch from neuronal to glial gene expression and dysregulates expression of Sox2 and its regulator, genes vital for stem cell pluripotency and for the neuronal/glial cell fate decision. In addition, HPRT deficiency dysregulates many cellular functions controlling cell cycle and proliferation mechanisms, RNA metabolism, DNA replication and repair, replication stress, lysosome function, membrane trafficking, signaling pathway for platelet activation (SPPA) multiple neurotransmission systems and sphingolipid, sulfur and glycan metabolism. We propose that the neural aberrations of HPRT deficiency result from combinatorial effects of these multi-system metabolic errors. Since some of these aberrations are also found in forms of Alzheimer's and Huntington's disease, we predict that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may therefore provide new experimental opportunities for clarifying pathogenesis and for devising new potential therapeutic targets in developmental and genetic disease.
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