Editors' ChoiceDevelopmental Biology

Dicer Switch

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Science Signaling  16 Dec 2014:
Vol. 7, Issue 356, pp. ec348
DOI: 10.1126/scisignal.aaa4715

The RNAse Dicer is required for the processing of precursor RNAs into mature microRNAs (miRNAs) and small-interfering RNAs (siRNAs) in the cytoplasm. In several species, including the nematode Caenorhabditis elegans and mouse, Dicer is important for oocyte maturation and embryogenesis. C. elegans mitogen-activated protein kinase 1 (MPK-1), which is homologous to mammalian extracellular signal–regulated kinases (ERK1 and ERK2), is required for oogenesis and oocyte maturation. MPK-1 is active throughout most stages of oogenesis, but is transiently inactivated as oocytes progress through the loop region of the gonad and then again inhibited immediately prior to fertilization. Drake et al. report that mouse ERK2 phosphorylated C. elegans Dicer 1 (DCR-1) on two conserved serine residues (Ser1705 and Ser1833) in vitro. Phosphorylated DCR-1 (pDCR-1) was present in the nuclei of oocytes throughout most of oogenesis, but disappeared just prior to fertilization. No pDCR-1 was present in oocytes in mpk-1 mutant worms. Experiments with engineered nonphosphorylatable and phosphomimetic forms of DCR-1 indicated that phosphorylation was both necessary and sufficient for nuclear accumulation of DCR-1. Genetic mosaic experiments demonstrated that DCR-1 was required in somatic cells for oogenesis and in the germline for embryogenesis. Experiments testing the ability of wild-type, nonphosphorylatable, and phosphomimetic forms of DCR-1 to rescue the phenotypes of dcr-1 mutants showed that phosphorylation of DCR-1 on Ser1705 was required for oogenesis and that phosphorylation of DCR-1 on Ser1833 was required for the transient inhibition of MPK-1 in the loop region of the gonad, suggesting the presence of a negative feedback mechanism. In vitro, murine ERK2 phosphorylated human Dicer on Ser1728 and Ser1852, which are homologous to Ser1705 and Ser1833 of C. elegans DCR-1. In cultured human cells, ERK activation was required for nuclear translocation of phosphorylated Dicer upon fibroblast growth factor stimulation, indicating that ERK-mediated control of Dicer localization is conserved. Whether nuclear localization inhibits Dicer activity or just alters its activity is not yet clear. Comparison of the miRNA profiles from wild-type and mutant animals expressing nonphosphorylatable or phosphomimetic forms of DCR-1 demonstrated that the phosphorylation status of DCR-1 affected miRNA processing, but further studies are needed to clarify the effect of phosphorylation on the activity of DCR-1. Oocyte and early embryos are transcriptionally silent, making posttranslational control of gene expression particularly important in these cells. Thus, an ERK-mediated switch in Dicer activity may regulate miRNA production and therefore gene regulation during oogenesis and in the oocyte-embryo transition.

M. Drake, T. Furuta, K. M. Suen, G. Gonzalez, B. Liu, A. Kalia, J. E. Ladbury, A. Z. Fire, J. B. Skeath, S. Arur, A requirement for ERK-dependent Dicer phosphorylation in coordinating oocyte-to-embryo transition in C. elegans. Dev. Cell 31, 614–628 (2014). [PubMed]

F. Hu, E. C. Lai, K. Okamura, A signaling-induced switch in Dicer localization and function. Dev. Cell 31, 523–524 (2014). [PubMed]

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