MicroRNAs (miRNAs) are small regulatory RNAs that are between 21 and 25 nucleotides in length and repress gene function through interactions with target mRNAs. The genomes of metazoans encode on the order of several hundred miRNAs, but the processes they regulate have been defined for only two in C. elegans. We searched for new inhibitors of apoptotic cell death by testing existing collections of P element insertion lines for their ability to enhance a small-eye phenotype associated with eye-specific expression of the Drosophila cell death activator Reaper. Here we report the identification of the Drosophila miRNA mir-14 as a cell death suppressor. Loss of mir-14 enhances Reaper-dependent cell death, whereas ectopic expression suppresses cell death induced by multiple stimuli. Animals lacking mir-14 are viable. However, they are stress sensitive and have a reduced lifespan. Mir-14 mutants have elevated levels of the apoptotic effector caspase Drice, suggesting one potential site of action. Mir-14 also regulates fat metabolism. Deletion of mir-14 results in animals with increased levels of triacylglycerol and diacylglycerol, whereas increases in mir-14 copy number have the converse effect. We discuss possible relationships between these phenotypes.

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The Drosophila let-7-Complex (let-7-C) is a polycistronic locus encoding three ancient microRNAs: let-7, miR-100, and fly lin-4 (miR-125). We find that the let-7-C locus is principally expressed in the pupal and adult neuromusculature. let-7-C knockout flies appear normal externally but display defects in adult behaviors (e.g., flight, motility, and fertility) as well as clear juvenile features in their neuromusculature. We find that the function of let-7-C to ensure the appropriate remodeling of the abdominal neuromusculature during the larval-toadult transition is carried out predominantly by let-7 alone. This heterochronic role of let-7 is likely just one of the ways in which let-7-C promotes adult behavior.Supplemental material is available at http://www.genesdev.org.Received March 10, 2008; revised version accepted April 11, 2008. Mutations in heterochronic genes in Caenorhabditis elegans cause cells in particular lineages to express their stage-specific fates earlier or later than normal (Ambros and Horvitz 1984). Detailed analysis of these genes has revealed a regulatory pathway of heterochronic genes that specifies the timing of cellular development in diverse cell types and thereby ensures a coordinated schedule of developmental events throughout the worm (for review, see Rougvie 2005; Moss 2007). The existence of the heterochronic gene pathway in worms and the conservation of some of its components through animal evolution suggest that functionally analogous pathways could also coordinate developmental timing in higher organisms . Two of these highly conserved components of the heterochronic pathway, let-7 and lin-4, are microRNAs (miRNAs), a class of small RNAs that post-transcriptionally modulate the expression of target transcripts (for review, see Jackson and Standart 2007). The sequences and developmentally regulated expression profiles of let-7 and lin-4 are conserved among diverse bilaterians Sempere et al. 2003). For example, Drosophila let-7 and miR-125 (fly lin-4) are robustly up-regulated during metamorphosis, as is another highly conserved miRNA, miR-100 Sempere et al. 2002Sempere et al. , 2003Bashirullah et al. 2003). All three of these ancient miRNAs are encoded in a 1-kb region of the Drosophila genome ( Fig. 1; Sempere et al. 2003), and their clustered organization has been conserved and duplicated in vertebrates (Supplemental Fig. S1; Sempere et al. 2003;Prochnik et al. 2007). These findings suggest that miR-100, let-7, and miR-125 coordinately control gene expression to regulate developmental timing in animals.To test this hypothesis, we analyzed the roles of miR-100, let-7, and miR-125 in Drosophila and find that these miRNAs are required for normal adult behavior, suggesting roles in neural development and/or function. let-7 in particular is required for remodeling of the fly neuromusculature during the larval-to-adult transition, confirming that a general developmental timing function of let-7 has been evolutionarily conserved from worms to flies. Results and DiscussionThe clus...

Summary In addition to establishing dendritic coverage of the receptive field, neurons need to adjust their dendritic arbors to match changes of the receptive field. Here we show that dendrite arborization (da) sensory neurons establish dendritic coverage of the body wall early in Drosophila larval development and then grow in precise proportion to their substrate, the underlying body wall epithelium, as the larva more than triples in length. This phenomenon, referred to as scaling growth of dendrites, requires the function of the microRNA (miRNA) bantam (ban) in the epithelial cells rather than the da neurons themselves. We further show that ban in epithelial cells dampens Akt kinase activity in adjacent neurons to influence dendrite growth. This signaling between epithelial cells and neurons receiving sensory input from the body wall synchronizes their growth to ensure proper dendritic coverage of the receptive field.