The RNA-editing protein ADAR is essential for early development in the mouse. Genetic evidence suggests that A to I editing marks endogenous RNAs as 'self'. Today, different Adar knockout alleles have been generated that show a common phenotype of apoptosis, liver disintegration, elevated immune response and lethality at E12.5. All the Adar knockout alleles can be rescued by a concomitant deletion of the innate immunity genes Mavs or Ifih1 (MDA5), albeit to different extents. This suggests multiple functions of ADAR. We analyze AdarΔ7-9 mice that show a unique growth defect phenotype when rescued by Mavs. We show that AdarΔ7-9 can form a truncated, unstable, editing deficient protein that is mislocalized. Histological and hematologic analysis of these mice indicate multiple tissue- and hematopoietic defects. Gene expression profiling shows dysregulation of Rps3a1 and Rps3a3 in rescued AdarΔ7-9. Consistently, a distortion in 40S and 60S ribosome ratios is observed in liver cells. This dysregulation is also seen in AdarΔ2-13; Mavs-/- but not in AdarE861A/E861A; Ifih1-/- mice, suggesting editing-independent functions of ADAR in regulating expression levels of Rps3a1 and Rps3a3. In conclusion, our study demonstrates the importance of ADAR in post-natal development which cannot be compensated by ADARB1.

中文翻译：

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MAVS缺乏挽救的ADAR的内部缺失导致微小的表型。

RNA编辑蛋白ADAR对于小鼠的早期发育至关重要。遗传证据表明A至I编辑将内源性RNA标记为“自身”。如今，已经产生了不同的Adar基因敲除等位基因，这些基因在E12.5处显示出常见的细胞凋亡，肝崩解，免疫反应增强和致死性表型。可以通过先天免疫基因Mavs或Ifih1（MDA5）的同时缺失来挽救所有的Adar基因敲除等位基因，尽管程度不同。这表明了ADAR的多种功能。我们分析了被小牛抢救时显示独特的生长缺陷表型的AdarΔ7-9小鼠。我们显示，AdarΔ7-9可以形成截短的，不稳定的，编辑缺陷的，定位错误的蛋白质。这些小鼠的组织学和血液学分析表明存在多种组织和造血缺陷。基因表达谱显示在拯救的AdarΔ7-9中Rps3a1和Rps3a3失调。一致地，在肝细胞中观察到40S和60S核糖体比率的扭曲。这种失调也可见于AdarΔ2-13中。小牛-/-，但不在AdarE861A / E861A中；Ifih1-/-小鼠提示ADAR在调节Rps3a1和Rps3a3表达水平中的编辑独立功能。总之，我们的研究证明了ADAR在产后发育中的重要性，而ADARB1不能弥补这一缺陷。