, 2010), and some exciting insights have been made into signal or state-dependent activation of such players (e.g.,

Banerjee et al., 2009), a key question is how are individual genes targeted for specific regulation? Although multiple RG 7204 classes of sequence-specific RNA regulatory mechanisms contribute to shaping the functional landscape, and there are significant interactions between these molecular regulators, we will focus on microRNA (miRNA)-mediated control over the maturation and plasticity of neurons and their synaptic connections, highlighting primarily observations made in the past few years. miRNAs were first identified based on classical genetics as regulators of developmental timing in Caenorabditis elegans ( Lee et al., 1993; Reinhart et al., 2000). These short noncoding RNA were then found in other organisms by virtue of striking sequence conservation across species ( Pasquinelli et al., 2000). miRNA genes are transcribed

as RNA polymerase II or III transcripts (pri-miRNA) that are processed by specific SCR7 nuclease cleavage (or RNA splicing for miRtrons) to produce short hairpin RNAs (pre-miRNA) that are transported out of the nucleus and then cleaved once more to generate mature miRNAs that can be loaded into protein complexes that allow binding to specific target mRNA ( Figure 1C; reviewed by Bartel and Chen, 2004). Mature miRNA-target mRNA pairs are formed by proteins in the Argonaute (Ago) family together with other components of the RNA-induced silencing complex (RISC; Du and Zamore, 2005). Although there are exceptions, miRNAs inhibit expression for most target genes by reducing steady-state message levels ( Guo et al., 2010), although this may occur after an initial blockade of translation ( Bazzini et al.,

2012; Djuranovic et al., 2012). Many rounds of transcriptome secondly sequence and expression analysis have uncovered a large number of miRNA genes spanning all multicellular organisms (see http://www.mirbase.org; Griffiths-Jones et al., 2006). Among animal species, the number of miRNA genes has expanded dramatically with increasing organismal complexity (i.e., numbers of differentiated cell types), contributing to speculation that despite high conservation in many miRNA families, diversification of other miRNA genes has contributed significantly to the evolution of different metazoan body plans (Sempere et al., 2006). For example, Cnidarian genomes contain tens of miRNA genes (e.g., 17 in Hydra and 49 in Nematostella), whereas Ecdysozoa have roughly 5- to 10-fold more (e.g., 223 in C. elegans and 240 in D. melanogaster), and Humans have over 1,500 (http://www.mirbase.org).