Cutting out circular RNAs: Circular RNAs are widespread, but their functions have been controversial. Piwecka et al. used CRISPR-Cas9 technology to remove the locus encoding the circular RNA Cdr1as from the mouse genome. Single-cell electrophysiological measurements in excitatory neurons revealed an increase in spontaneous vesicle release from the knockout mice and depression in the synaptic response with two consecutive stimuli, indicating that Cdr1as deficiency leads to dysfunction of excitatory synaptic transmission. Small RNA sequencing of several major regions of the brain showed that expression of two microRNAs, miR-7 and miR-671, that bind to Cdr1as decreased and increased, respectively. These results, along with expression analyses, suggest that neuronal Cdr1as stabilizes or transports miR-7, which in turn represses genes that are early responders to different stimuli. Science , this issue p. eaam8526

The let‐7 miRNA regulates developmental timing in C. elegans and is an important paradigm for investigations of miRNA functions in mammalian development. We have examined the role of miRNA precursor processing in the temporal control and lineage specificity of the let‐7 miRNA. In situ hybridization (ISH) in E9.5 mouse embryos revealed early induction of let‐7 in the developing central nervous system. The expression pattern of three let‐ 7 family members closely resembled that of the brain‐enriched miRNAs mir‐124, mir‐125 and mir‐128 . Comparison of primary, precursor, and mature let‐7 RNA levels during both embryonic brain development and neural differentiation of embryonic stem cells and embryocarcinoma (EC) cells suggest post‐transcriptional regulation of let‐7 accumulation. Reflecting these results, let‐7 sensor constructs were strongly down‐regulated during neural differentiation of EC cells and displayed lineage specificity in primary cells. Neural differentiation of EC cells was accompanied by an increase in let‐ 7 precursor processing activity in vitro . Furthermore, undifferentiated and differentiated cells contained distinct precursor RNA binding complexes. A neuron‐enhanced binding complex was shown by antibody challenge to contain the miRNA pathway proteins Argonaute1 and FMRP. Developmental regulation of the processing pathway correlates with differential localization of the proteins Argonaute, FMRP, MOV10, and TNRC6B in self‐renewing stem cells and neurons.—Wulczyn, F. G., Smirnova, L., Rybak, A., Brandt, C., Kwidzinski, E., Ninnemann, O., Strehle, M., Seiler, A., Schumacher, S., Nitsch, R. Post‐transcriptional regulation of the let‐7 microRNA during neural cell specification. FASEB J. 21, 415–426 (2007)