Asxl1 ablation in mouse embryonic stem cells impairs neural differentiation without affecting self-renewal

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Additional sex comb-like1 (Asxl1) is known as a chromatin modulator that plays dual functions in transcriptional regulation depending on the cell type. Recent studies using <I>Asxl1</I> knockout mice revealed that Asxl1 is important for the proliferation and differentiation of hematopoietic progenitor cells, and the development of organs. Although we previously reported <I>Asxl1</I> as a Sox2 target gene, its function in embryonic stem cells (ESCs) remains largely unknown. For this purpose, we isolated ESCs from the blastocyst inner cell mass of <I>Asxl1</I> <SUP>−/−</SUP> mice. <I>Asxl1</I> deficiency in ESCs exhibited no effect on cell proliferation, expression of core pluripotent transcription factors, or alkaline phosphatase activity, suggesting dispensability of Asxl1 for self-renewal of ESCs. By contrast, the differentiation of <I>Asxl1</I> <SUP> <I>−/−</I> </SUP> ESCs was significantly affected as shown by size reductions of embryoid bodies accompanied with apoptosis, aberrant expression of differentiation genes, downregulation of bivalent neurogenesis genes, and abnormal axon formation in neurons. Overall, our findings indicated that Asxl1 played a critical role in regulating genes associated with neural differentiation without affecting self-renewal of mouse ESCs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> <I>Asxl1</I> is dispensable for the maintenance of ESC self-renewal and pluripotency. </LI> <LI> <I>Asxl1</I> deficiency leads to defective EB formation. </LI> <LI> Differentiation-associated genes are dysregulated in <I>Asxl1</I>-deleted EBs. </LI> <LI> <I>Asxl1</I> is required for the proper morphology of neuronal axons. </LI> </UL> </P>