Furthermore, we detected a corresponding decrease in the proportion of TBR2+ intermediate progenitor cells, whose identity is antagonized by active Notch signaling (Yoon et al
Furthermore, we detected a corresponding decrease in the proportion of TBR2+ intermediate progenitor cells, whose identity is antagonized by active Notch signaling (Yoon et al., 2008; Shimojo et al., 2008). cells (RGCs) in the ventricular and subventricular zones of developing human brain. Down-regulation in neuroblastoma cells reduced cell proliferation and induced neuronal differentiation, an effect phenocopied by miR-143-3p over-expression. Gain-of-function of in developing mouse cortex led to an expansion of PAX6+ RGCs. These findings support role for in miRNA-mediated regulation of Notch signaling within the neural progenitor pool in primates that may have contributed to the expansion of cerebral cortex. Introduction Long non-coding RNAs (lncRNAs) have complex and diverse functions in brain development. lncRNAs have relatively low levels of evolutionary conservation with sequence deletions, insertions (Mclean et al., 2003) and accelerated nucleotide substitution (Pollard et al., 2006) at evolutionary divergences. About a third of the lncRNAs are unique to Verteporfin the primate lineage (Derrien et al., 2012), and only ~12% of human lncRNAs appear to be conserved in other vertebrate species (Ulitsky and Bartel, 2013; Cabili et al., 2011). The restricted spatial and Verteporfin temporal expression patterns of many lncRNAs within the brain likely contributes to neuronal diversification in large brain primates (Amaral and Mattick, 2008; Cao et al., 2006; Chodroff et al., 2010; Qureshi et al., 2010) and the specification of individual neuronal subtypes (Mercer et al., 2008). MicroRNAs (miRNAs) are derived from hairpin precursors that function in association with Argonaute proteins to regulate target genes post-transcriptionally. These ~ 21C23 nucleotide sequences change quite dramatically as cells transition from germ cells to neural stem cells and at all stages of cell differentiation during brain development (reviewed in Fineberg et al., 2009). The many regulatory controls over miRNA levels and cell type specific expression, include the well-known panoply of gene expression mechanisms, e.g. promoters, enhancers and epigenetic modifications; as well as degradation and biogenesis pathways (Ha and Kim, 2014). An additional source of control over the levels of mature miRNAs is their sequestration and release from binding sites, known as miRNA response elements Verteporfin (MREs) in transcribed pseudogenes, long non-coding RNAs (lncRNAs) and circular RNAs (Cesana et al., 2011; Ebert and Sharp, 2010; Hansen et al., 2013; Kallen et al., 2013; Memczak et al., 2013; Tay et CD114 al., 2011, 2014; Wang et al., 2013; Zhang et al., 2013). These natural miRNA-binding platforms known as sponges contain MREs that can relieve mRNA targets from repression or indirectly induce target mRNA repression by release of miRNAs from this reservoir. Natural miRNA sponges impart stability to miRNAs (Bail et al., 2010) by sequence-specifically sequestering miRNAs directed toward specific mRNA targets within Argonaute protein complexes. Verteporfin Short stretches of complementarity to miRNA seeds in regions of relatively unstructured RNA found in lncRNAs could evolve easily (Ebert and Sharp, 2010). Verteporfin lncRNAs have the potential to sponge miRNAs, and thereby, regulate the expression of mRNAs (Hu et al., 2012; Wang et al., 2013; Wang et al., 2010; Kallen et al., 2013; Tay et al., 2014; Cesana et al., 2011). The first of these was discovered in plants (Franco-Zorrilla et al., 2007) and others have been described during muscle development (Legnini et al., 2014; Cesana et al., 2011; Kallen et al., 2013), and in embryonic stem cells to regulate core pluripotency transcription factors (Wang et al., 2013). The lncRNA has been detected in a complex with miR-17-5p by photo-crosslinking and Argonaute 2 immunopurification (Imig et al., 2014). We identified and functionally characterized a lncRNA, (lncRNA for Neuronal Development) that is deleted in a region of the genome associated with a human neurodevelopmental disorder. A microdeletion at 2p25.3 includes and 6C7 protein-coding genes (Stevens et al., 2011; Rio et al., 2013; Doco-Fenzy et al., 2014; Bonaglia et al., 2014). Six individuals harboring 2p25.3.