Search

The production of two distinct functional microRNAs from opposite DNA strands by a single Hox locus in Drosophila is discussed.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.09.020 Byline: Janina S. Karres (1), Valerie Hilgers (1), Ines Carrera (3), Jessica Treisman (3), Stephen M. Cohen (1)(2) Keywords: RNA; CELLBIO; MOLNEURO Abstract: microRNAs (miRNAs) bind to specific messenger RNA targets to posttranscriptionally modulate their expression. Understanding the regulatory relationships between miRNAs and targets remains a major challenge. Many miRNAs reduce expression of their targets to inconsequential levels. It has also been proposed that miRNAs might adjust target expression to an optimal level. Here we analyze the consequences of mutating the conserved miRNA miR-8 in Drosophila. We identify atrophin as a direct target of miR-8. miR-8 mutant phenotypes are attributable to elevated atrophin activity, resulting in elevated apoptosis in the brain and in behavioral defects. Reduction of atrophin levels in miR-8-expressing cells to below the level generated by miR-8 regulation is detrimental, providing evidence for a 'tuning target' relationship between them. Drosophila atrophin is related to the atrophin family of mammalian transcriptional regulators, implicated in the neurodegenerative disorder DRPLA. The regulatory relationship between miR-8 and atrophin orthologs is conserved in mammals. Author Affiliation: (1) European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany (2) Temasek Life Sciences Laboratory, and Department of Biological Sciences, National University of Singapore, 1 Research Link, Singapore 117604 (3) Skirball Institute, New York University, 540 First Avenue, New York, NY 10016, USA Article History: Received 8 November 2006; Revised 22 August 2007; Accepted 14 September 2007 Article Note: (miscellaneous) Published: October 4, 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.04.013 Byline: Ya-Wen Chen (a), Johannes W. Pedersen (b), Hans H. Wandall (b), Steven B. Levery (c), Sandrine Pizette (a), Henrik Clausen (c), Stephen M. Cohen (a) Keywords: Egghead; Brainiac; Glycosyltransferase; Glycolipid; Glycosylation; CG8536; CG14517; CG17223; CG5878 Abstract: Glycosphingolipids (GSL) are glycosylated polar lipids in cell membranes essential for development of vertebrates as well as Drosophila. Mutants that impair enzymes involved in biosynthesis of GSL sugar chains provide a means to assess the functions of the sugar chains in vivo. The Drosophila glycosyltransferases Egghead and Brainiac are responsible for the 2nd and 3rd steps of GSL sugar chain elongation. Mutants lacking these enzymes are lethal and the nature of the defects that occur has suggested that GSL might impact on signaling by the Notch and EGFR pathways. Here we report on characterization of enzymes involved in the 4th and 5th steps of GSL sugar chain elongation in vitro and explore the biological consequences of removing the enzymes involved in step 4 in vivo. Two [beta]4-N-Acetylgalactosyltransferase enzymes can carry out step 4 ([beta]4GalNAcTA and [beta]4GalNAcTB), and while they may have overlapping activity, the mutants produce distinct phenotypes. The [beta]4GalNAcTA mutant displays behavioral defects, which are also observed in viable brainiac mutants, suggesting that proper locomotion and coordination primarily depend on GSL elongation. [beta]4GalNAcTB mutant animal shows ventralization of ovarian follicle cells, which is caused by defective EGFR signaling between the oocyte and the dorsal follicle cells to specify dorsal fate. GSL sequentially elongated by Egh, Brn and [beta]4GalNAcTB in the oocyte contribute to this signaling pathway. Despite the similar enzymatic activity, we provide evidence that the two enzymes are not functionally redundant in vivo, but direct distinct developmental functions of GSL. Author Affiliation: (a) Developmental Biology Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany (b) Institute of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark (c) Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA Article History: Received 31 January 2007; Revised 27 March 2007; Accepted 11 April 2007

Post-transcriptional gene regulation by the microRNA miR9a plays an important role in ensuring the precision of sense organ specification in Drosophila. The function of miR-9a is reported by generating a targeted knockout of a precursor hairpin in Drosophila melanogaster.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.07.013 Byline: Barry J. Thompson (1), Stephen M. Cohen (1) Abstract: The Hippo signaling pathway acts upon the Yorkie transcriptional activator to control tissue growth in Drosophila. Activated Yorkie drives growth by stimulating cell proliferation and inhibiting apoptosis, but how it achieves this is not understood. Yorkie is known to activate Cyclin E (CycE) and the apoptosis inhibitor DIAP1. However, overexpression of these targets is not sufficient to cause tissue overgrowth. Here we show that Yorkie also activates expression of the bantam microRNA, a known regulator of both proliferation and apoptosis. bantam overexpression mimics Yorkie activation while loss of bantam function slows the rate of cell proliferation. bantam is necessary for Yorkie-induced overproliferation and bantam overexpression is sufficient to rescue survival and proliferation of yorkie mutant cells. Finally, we show that bantam levels are regulated during both developmentally programmed proliferation arrest and apoptosis. In summary, the results show that the Hippo pathway regulates expression of bantam to control tissue growth in Drosophila. Author Affiliation: (1) European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg 69117, Germany Article History: Received 28 February 2006; Revised 12 May 2006; Accepted 5 July 2006 Article Note: (miscellaneous) Published: August 24, 2006

Evidence to show that the microRNA miR-278 plays a role in the control of energy homeostasis in Drosophila is presented. miR-278 acts by a different mechanism, at least partly through regulation of expanded transcript to control insulin sensitivity in adipose and peripheral tissues.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.11.023 Byline: Alexander Stark (1), Julius Brennecke (1), Natascha Bushati (1), Robert B. Russell (1), Stephen M. Cohen (1) Abstract: MicroRNAs are small noncoding RNAs that serve as posttranscriptional regulators of gene expression in higher eukaryotes. Their widespread and important role in animals is highlighted by recent estimates that 20%-30% of all genes are microRNA targets. Here, we report that a large set of genes involved in basic cellular processes avoid microRNA regulation due to short 3'UTRs that are specifically depleted of microRNA binding sites. For individual microRNAs, we find that coexpressed genes avoid microRNA sites, whereas target genes and microRNAs are preferentially expressed in neighboring tissues. This mutually exclusive expression argues that microRNAs confer accuracy to developmental gene-expression programs, thus ensuring tissue identity and supporting cell-lineage decisions. Author Affiliation: (1) European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany Article History: Received 15 July 2005; Revised 27 September 2005; Accepted 14 November 2005 Article Note: (miscellaneous) Published online: December 1, 2005

An enormous regulatory potential for microRNA (miRNAs) in gene expression programs, rivaling the complexity of the transcriptional control network is suggested. Understanding the role of miRNAs leads inevitably to the question of why certain gene expression events are targeted by miRNAs rather than by transcriptional repressors.

The relevance of 4E-BP function, an important regulator of overall translation levels in cells, for organismal development is discussed and evidence for an alternate view is presented. It is suggested that 4E-BP works as a metabolic break that is activated under conditions of environmental stress to control fat metabolism.

The Hedgehog signaling pathway plays an essential role in the pattern formation and development of metazoan animals. Misregulation of Hedgehog signaling has also been associated with the formation of multiple types of cancer. For these reasons, the Hedgehog pathway has attracted considerable interest. Many proteins required in the Hedgehog pathway have been identified, and while much has been learned about their function in signal transduction, it is clear that this complement of proteins does not comprise the full set necessary for Hedgehog signal transduction. Because significant gaps remain in our knowledge of the molecules required for Hedgehog signaling, we performed an enhancer/suppressor screen in Drosophila melanogaster to identify novel components of the pathway. In addition to the isolation of new alleles of the known pathway components patched and smoothened, this screen identified 14 novel complementation groups and a larger number of loci represented by single alleles. These groups include mutations in the genes encoding the translation factors eRF1 and eIF1A and the kinesin-like protein Pavarotti. It also identified mutations in a gene whose product is necessary for the movement of Hedgehog protein through tissues.

20-hydroxyecdysone was discovered as the major biologically active insect steroid hormone half a century ago, yet much remains to be learned about its biosynthesis and its activities. 20-hydroxyecdysone controls many biological processes, including progression between larval stages, entry to pupariation and metamorphosis. A number of genes required for 20-hydroxyecdysone production have been identified, including those encoding enzymes that mediate four of the late steps of biosynthesis. A second smaller group of low ecdysone mutants do not encode enzymes. Here, we report identification of one such gene, which we call molting defective, on the basis of its lethal phenotype. molting defective encodes a nuclear zinc finger protein required for ecdysone biosynthesis. Keywords: Ecdysone; Steroid hormone; Ring gland; Molting hormone; Halloween genes

The Drosophila Sterile-20 kinase Slik promotes tissue growth during development by stimulating cell proliferation and by preventing apoptosis. It is observed that Slik acts via distinct pathways to coordinate cell proliferation with epithelial cell behavior during tissue growth.

Antennapedia is one of the homeotic selector genes required for specification of segment identity in Drosophila. Dominant mutations that ectopically express Antennapedia cause transformation of antenna to leg. Loss-of-function mutations cause partial transformation of leg to antenna. Here we examine the role of Antennapedia in the establishment of leg identity in light of recent advances in our understanding of antennal development. In Antennapedia mutant clones in the leg disc, Homothorax and Distal-less are coexpressed and act via spineless to transform proximal femur to antenna. Antennapedia is negatively regulated during leg development by Distal-less, spineless, and dachshund and this reduced Antennapedia expression is needed for the proper development of distal leg elements. These findings suggest that the temporal and spatial regulation of the homeotic selector gene Antennapedia in the leg disc is necessary for normal leg development in Drosophila. Keywords: Drosophila; Leg development; Antp; Dll; hth; ss; dac