Abstract
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.
Highlights
Cell fate relies on the correct “read” of the genetic code and its translation into functional proteins
In order to understand the biological function of SMG6 in the differentiation program of committed lineage neuroprogenitor cells (NPCs) in the central nervous system (CNS), we generated a conditional knockout mouse model in which Smg6 was deleted in NPCs from embryonic day E10.5 by intercrossing Smg6F/∆ [13] and Nestin-Cre transgenic mice [27]
We previously showed that Smg6 deletion in embryonic stem (ES) cells had no impact on their viability but blocked their ability to differentiate into germ layers during mouse development
Summary
Cell fate relies on the correct “read” of the genetic code and its translation into functional proteins. Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that is involved in controlling the quality of mRNA [1,2,3]. After a nonsense mutation or alternative splicing events, harbor a premature termination codon (PTC) before (>50–55 nucleotides) an exon–exon junction complex (EJC). The stable interaction of UPF1 with eRFs at the PTC site recruits the NMD factors UPF2, UPF3 and the kinase SMG1. SMG1 phosphorylates UPF1 and UPF2 thereby promoting the recruitment of the endonuclease SMG6 or the SMG5/SMG7-mediated exonuclease for RNA degradation [1]. The branches of SMG6- and SMG5/7-mediated NMD pathways have been shown to overlap, yet with distinct differences in certain populations of target transcripts [4]
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