Program in Neuroscience, Stony Brook University, Stony Brook, New York 11794, USA.
RNA. 2012 Apr;18(4):704-19. doi: 10.1261/rna.030742.111. Epub 2012 Feb 13.
The molecular mechanisms that govern the timing and fate of neural stem-cell differentiation toward the distinct neural lineages of the nervous system are not well defined. The contribution of post-transcriptional regulation of gene expression to neural stem-cell maintenance and differentiation, in particular, remains inadequately characterized. The RNA-binding protein Hnrpab is highly expressed in developing nervous tissue and in neurogenic regions of the adult brain, but its role in neural development and function is unknown. We raised a mouse that lacks Hnrpab expression to define what role, if any, Hnrpab plays during mouse neural development. We performed a genome-wide quantitative analysis of protein expression within the hippocampus of newborn mice to demonstrate significantly altered gene expression in mice lacking Hnrpab relative to Hnrpab-expressing littermates. The proteins affected suggested an altered pattern of neural development and also unexpectedly indicated altered glutamate signaling. We demonstrate that Hnrpab(-/-) neural stem and progenitor cells undergo altered differentiation patterns in culture, and mature Hnrpab(-/-) neurons demonstrate increased sensitivity to glutamate-induced excitotoxicity. We also demonstrate that Hnrpab nucleocytoplasmic distribution in primary neurons is regulated by developmental stage.
调控神经干细胞向神经系统不同神经谱系分化的时间和命运的分子机制尚未明确。特别是，基因表达的转录后调控对神经干细胞的维持和分化的贡献还没有得到充分的描述。RNA 结合蛋白 Hnrpab 在发育中的神经组织和成年大脑的神经发生区域中高度表达，但它在神经发育和功能中的作用尚不清楚。我们培育了一种缺乏 Hnrpab 表达的小鼠，以确定 Hnrpab 在小鼠神经发育过程中是否发挥作用。我们对新生小鼠海马体中的蛋白质表达进行了全基因组定量分析，结果表明，与表达 Hnrpab 的同窝仔鼠相比，缺乏 Hnrpab 的小鼠的基因表达有显著改变。受影响的蛋白质表明神经发育模式发生了改变，也出人意料地表明谷氨酸信号发生了改变。我们证明 Hnrpab(-/-)神经干细胞和祖细胞在培养中经历了改变的分化模式，成熟的 Hnrpab(-/-)神经元对谷氨酸诱导的兴奋毒性表现出更高的敏感性。我们还证明，初级神经元中 Hnrpab 的核质分布受发育阶段的调节。
