O-GLcNAc post-translational modifications regulate the entry of neurons into an axon branching program.
O-GLcNAc post-translational modifications regulate the entry of neurons into an axon branching program.
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DOI：
10.1002/dneu.20695
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发表时间：
2009-02-01
影响因子：
3
通讯作者：
Gallo, Gianluca
中科院分区：
文献类型：
--
作者：
Francisco, Herb;Kollins, Katherine;Varghis, Neal;Vocadlo, David;Vosseller, Keith;Gallo, Gianluca
在丝氨酸和苏氨酸上可逆地添加O-linked n -乙酰氨基葡萄糖（O-GlcNAc）可以修饰许多神经元细胞质和核蛋白。O-GlcNAc修饰在神经元发育中的细胞功能尚不清楚。我们报道了o - glcnac修饰的蛋白在培养的原代鸡前脑神经元中不均匀分布，在细胞体中有强烈的免疫染色，在轴突和所有突起中有间断的免疫染色，并且在丝状足/板足中有定位。O-GlcNAcase（从蛋白质中去除O-GlcNAc的酶）的过表达增加了轴突分支的神经元百分比，而不改变每个神经元轴突分支的频率，并增加了轴突丝状足的数量。相反，通过使用抑制剂9d特异性抑制O-GlcNAcase，从药理学上增加蛋白质上的O-GlcNAc水平，可以减少轴突丝状足的数量，但对轴突长度或分支没有影响。用另一种O-GlcNAcase抑制剂PUGNAc治疗，同样减少了轴突丝状足的数量。此外，由腺苷酸环化酶激活剂forskolin诱导的轴突分支被O-GlcNAcase的药理抑制所抑制。Western分析显示，O-GlcNAc水平调节一些PKA底物对forskolin的磷酸化。这些数据提供了O-GlcNAc修饰对原代培养神经元发育特异性影响的第一个证据，并表明O-GlcNAc在调节轴突形态中的特定作用。©2008 Wiley期刊公司中国生物医学工程学报（英文版），2009
Many neuronal cytosolic and nuclear proteins are post-translationally modified by the reversible addition of O-linked N-acetylglucosamine (O-GlcNAc) on serines and threonines. The cellular functions of O-GlcNAc modifications in neuronal development are not known. We report that O-GlcNAc-modified proteins are distributed nonuniformly throughout cultured primary chicken forebrain neurons, with intense immunostaining of the cell body, punctuate immunostaining in axons and all processes, and localization in filopodia/lamellipodia. Overexpression of O-GlcNAcase, the enzyme that removes O-GlcNAc from proteins, increased the percentage of neurons exhibiting axon branching without altering the frequency of axon branches on a per neuron basis and increased the numbers of axonal filopodia. Conversely, pharmacologically increasing O-GlcNAc levels on proteins through specific inhibition of O-GlcNAcase with the inhibitor 9d decreased the numbers of axonal filopodia, but had no effect on axon length or branching. Treatment with an alternative O-GlcNAcase inhibitor, PUGNAc, similarly decreased the number of axonal filopodia. Furthermore, axon branching induced by the adenylyl cyclase activator forskolin was suppressed by pharmacological inhibition of O-GlcNAcase. Western analysis revealed that O-GlcNAc levels regulate the phosphorylation of some PKA substrates in response to forskolin. These data provide the first evidence of O-GlcNAc modification-specific influences in neuronal development in primary culture, and indicate specific roles for O-GlcNAc in the regulation of axon morphology. © 2008 Wiley Periodicals, Inc. Develop Neurobiol 69: 162–173, 2009
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