ADAR3 is a catalytically inactive member of the family of adenosine deaminases acting on RNA (ADARs). Here we have investigated its function in the context of the developing mouse brain. The expression of ADAR3 gradually increases throughout embryogenesis and drops after birth. Using primary cortical neurons, we show that ADAR3 is only expressed in a subpopulation of in vitro differentiated neurons, which suggests specific functions rather than being a general regulator of ADAR editing in the brain. The analysis of the ADAR3 interactome suggested a role in mRNA stability and translation, and we show that expression of ADAR3 in a neuronal cell line that is otherwise ADAR3-negative changes the expression and stability of a large number of mRNAs. Notably, we show that ADAR3 associates with polysomes and inhibits translation. We propose that ADAR3 binds to target mRNAs and stabilizes them in non-productive polysome complexes. Interestingly, the expression of ADAR3 downregulates genes related to neuronal differentiation and inhibits neurofilament outgrowth in vitro. In summary, we propose that ADAR3 negatively regulates neuronal differentiation, and that it does so by regulating mRNA stability and translation in an editing-independent manner.

中文翻译：

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ADAR3 调节神经元分化并调节 mRNA 稳定性和翻译


ADAR3 是作用于 RNA 的腺苷脱氨酶家族 （ADAR） 的催化失活成员。在这里，我们研究了它在发育中的小鼠大脑背景下的功能。ADAR3 的表达在整个胚胎发生过程中逐渐增加，出生后下降。使用原代皮层神经元，我们表明 ADAR3 仅在体外分化神经元的亚群中表达，这表明特定功能，而不是大脑中 ADAR 编辑的一般调节因子。对 ADAR3 相互作用组的分析表明在 mRNA 稳定性和翻译中发挥作用，我们表明 ADAR3 在其他 ADAR3 阴性的神经元细胞系中的表达会改变大量 mRNA 的表达和稳定性。值得注意的是，我们表明 ADAR3 与多核糖体结合并抑制翻译。我们提出 ADAR3 与靶 mRNA 结合并将它们稳定在非生产性多核糖体复合物中。有趣的是，ADAR3 的表达在体外下调与神经元分化相关的基因并抑制神经丝生长。总之，我们提出 ADAR3 负向调节神经元分化，并且它通过以不依赖编辑的方式调节 mRNA 稳定性和翻译来实现这一点。