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Mettl5 mediated 18S rRNA N6-methyladenosine (m6A) modification controls stem cell fate determination and neural function
Genes & Diseases ( IF 6.9 ) Pub Date : 2020-07-17 , DOI: 10.1016/j.gendis.2020.07.004
Lu Wang 1, 2 , Yu Liang 1, 2 , Rongzhi Lin 3 , Qiuchan Xiong 4 , Peng Yu 1 , Jieyi Ma 1 , Maosheng Cheng 1 , Hui Han 1 , Xiaochen Wang 1 , Ganping Wang 1 , Fengyin Liang 5 , Zhong Pei 5 , Demeng Chen 1 , Quan Yuan 4 , Yi-Zhou Jiang 2 , Shuibin Lin 1
Affiliation  

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.



中文翻译:

Mettl5 介导的 18S rRNA N6-甲基腺苷 (m6A) 修饰控制干细胞命运决定和神经功能

核糖体 RNA (rRNA) 占细胞总 RNA 的 80% 以上,而对 rRNA 修饰的生理功能知之甚少。18S rRNA m 6 的突变甲基转移酶 METTL5 会导致患者出现智力障碍、小头畸形和面部畸形,但对其潜在机制知之甚少。在这项研究中,我们鉴定了 METTL5 蛋白复合物,并揭示了 METTL5 主要与 RNA 结合蛋白和核糖体蛋白相互作用。在功能上,我们发现 mESCs 中的 Mettl5 敲除导致颅面和神经发育异常。此外,使用 Mettl5 敲除小鼠模型,我们进一步证明 Mettl5 敲除小鼠表现出智力障碍,概括了人类表型。从机制上讲,我们发现 Mettl5 通过调节髓鞘形成过程来维持大脑功能和智力。我们的研究揭示了失调的 18S rRNA m 6之间的因果关系A 修饰和神经功能缺陷,支持 rRNA 修饰在人类疾病中的重要生理功能。

更新日期:2020-07-17
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