Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis

被引:8
作者
Guerra, Gabriela Maria [1 ,4 ]
May, Doreen [1 ]
Kroll, Torsten [1 ]
Koch, Philipp [1 ]
Groth, Marco [1 ]
Wang, Zhao-Qi [1 ,2 ]
Li, Tang-Liang [1 ,3 ]
Grigaravicius, Paulius [1 ]
机构
[1] Fritz Lipmann Inst FLI, Leibniz Inst Aging, Beutenbergstr 11, D-07745 Jena, Germany
[2] Friedrich Schiller Univ Jena, Fac Biol Sci, Beutenbergstr 11, D-07745 Jena, Germany
[3] Shandong Univ, State Key Lab Microbial Technol, 72 Binhai Rd, Qingdao 266237, Peoples R China
[4] Deutsch Rheuma Forschungszentrum DRFZ, Virchowweg 12, D-10117 Berlin, Germany
基金
中国国家自然科学基金;
关键词
SMG6; NMD; neurogenesis; neurodevelopmental syndromes; CHILDHOOD-ONSET SCHIZOPHRENIA; DLX HOMEOBOX GENES; DECAY PATHWAY; GABAERGIC NEURONS; PROGENITOR CELLS; NONSENSE; DIFFERENTIATION; MUTATIONS; STEM; EXPRESSION;
D O I
10.3390/cells10123365
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated Smg6 in murine embryonic neural stem cells. Nestin-Cre-mediated deletion of Smg6 in mouse neuroprogenitor cells (NPCs) caused perinatal lethality. Mutant mice brains showed normal structure at E14.5 but great reduction of the cortical NPCs and late-born cortical neurons during later stages of neurogenesis (i.e., E18.5). Smg6 inactivation led to dramatic cell death in ganglionic eminence (GE) and a reduction of interneurons at E14.5. Interestingly, neurosphere assays showed self-renewal defects specifically in interneuron progenitors but not in cortical NPCs. RT-qPCR analysis revealed that the interneuron differentiation regulators Dlx1 and Dlx2 were reduced after Smg6 deletion. Intriguingly, when Smg6 was deleted specifically in cortical and hippocampal progenitors, the mutant mice were viable and showed normal size and architecture of the cortex at E18.5. Thus, SMG6 regulates cell fate in a cell type-specific manner and is more important for neuroprogenitors originating from the GE than for progenitors from the cortex.
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页数:19
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