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Gene expression is a regulated process fueled by ATP consumption. Therefore, regulation must be coupled to constraints imposed by the level of energy metabolism. Here, we explore this relationship both theoretically and experimentally. A stylized mathematical model predicts that activators of gene expression have variable impact depending on metabolic rate. Activators become less essential when metabolic rate is reduced and more essential when metabolic rate is enhanced. We find that, in the Drosophila eye, expression dynamics of the yan gene are less affected by loss of EGFR-mediated activation when metabolism is reduced, and the opposite effect is seen when metabolism is enhanced. The effects are also seen at the level of pattern regularity in the adult eye, where loss of EGFR-mediated activation is mitigated by lower metabolism. We propose that gene activation is tuned by energy metabolism to allow for faithful expression dynamics in the face of variable metabolic conditions. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.01.058 Byline: Xin Li (1), Justin J. Cassidy (1), Catherine A. Reinke (1), Stephen Fischboeck (1), Richard W. Carthew (1) Keywords: RNA; DEVBIO Abstract: The microRNA miR-7 is perfectly conserved from annelids to humans, and yet some of the genes that it regulates in Drosophila are not regulated in mammals. We have explored the role of lineage restricted targets, using Drosophila, in order to better understand the evolutionary significance of microRNA-target relationships. From studies of two well characterized developmental regulatory networks, we find that miR-7 functions in several interlocking feedback and feedforward loops, and propose that its role in these networks is to buffer them against perturbation. To directly demonstrate this function for miR-7, we subjected the networks to temperature fluctuation and found that miR-7 is essential for the maintenance of regulatory stability under conditions of environmental flux. We suggest that some conserved microRNAs like miR-7 may enter into novel genetic relationships to buffer developmental programs against variation and impart robustness to diverse regulatory networks. Author Affiliation: (1) Department of Biochemistry, Molecular Biology and Cell Biology, 2205 Tech Drive, Northwestern University, Evanston, Illinois 60208, USA Article History: Received 16 May 2008; Revised 25 November 2008; Accepted 29 January 2009 Article Note: (miscellaneous) Published: April 16, 2009

A microRNa is a part of mechanism that makes cells sensitive to signals in the Drosophila eye. Expression of miR-7 is activated in cells as they begin differentiating into photoreceptors and this is dependent on EGF receptor signaling that triggers ERK-mediated degradation of the transcription factor Yan.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.10.040 Byline: Xin Li (1), Richard W. Carthew (1) Abstract: A critical question about signal transduction is how weak or transient activation of signaling pathways achieves a robust and long-term switch in gene expression. We report that a microRNA is part of a mechanism that makes cells sensitive to signals in the Drosophila eye. Expression of miR-7 is activated in cells as they begin differentiating into photoreceptors. This is dependent on EGF receptor (EGFR) signaling that triggers ERK-mediated degradation of the transcription factor Yan. In nonstimulated cells, Yan represses miR-7 transcription, whereas miR-7 RNA represses Yan protein expression in photoreceptors, by binding to sequences within its mRNA 3'UTR. We propose that reciprocal negative feedback between Yan and miR-7 ensures mutually exclusive expression, with Yan in progenitor cells and miR-7 in photoreceptor cells. Expression is switched when EGFR signaling transiently triggers Yan degradation. This two-tiered mechanism explains how signal transduction activity can robustly generate a stable change in gene-expression patterns. Author Affiliation: (1) Department of Biochemistry, Molecular Biology and Cell Biology, 2205 Tech Drive, Northwestern University, Evanston, Illinois 60208, USA Article History: Received 5 August 2005; Revised 7 October 2005; Accepted 31 October 2005 Article Note: (miscellaneous) Published: December 28, 2005

MicroRNAs (miRNAs) are a class of small RNAs that silence gene expression. In animal cells, miRNAs bind to the 3' untranslated regions of specific mRNAs and inhibit their translation. Although some targets of a handful of miRNAs are known, the number and identities of mRNA targets in the genome are uncertain, as are the developmental functions of miRNA regulation. To identify the global range of miRNA-regulated genes during oocyte maturation of Drosophila, we compared the proteome from wild-type oocytes with the proteome from oocytes lacking the dicer-1 gene, which is essential for biogenesis of miRNAs. Most identified proteins appeared to be subject to translation inhibition. Their transcripts contained putative binding sites in the 3' untranslated region for a subset of miRNAs, based on computer modeling. The fraction of genes subject to direct and indirect repression by miRNAs during oocyte maturation appears to be small (4%), and the genes tend to share a common functional relationship in protein biogenesis and turnover. The preponderance of genes that control global protein abundance suggests this process is under tight control by miRNAs at the onset of fertilization. translation control

Studies have uncovered new examples of RNA silencing in controlling endogenous gene expression and have revealed novel mechanisms of downregulation. It is found that the two main categories of small RNAs that lead directly into RNA silencing are- MicroRNAs and short interfering RNAs.

Author(s): Takashi Hayashi (corresponding author) [1, 2]; Richard W. Carthew (corresponding author) [1] Pattern formation is the process by which cells are spatially arranged into elaborate biological structures. Whereas significant [...]

Author(s): Ken-Ichi Takemaru [1, 2]; Shinji Yamaguchi [2, 3]; Young Sik Lee [3]; Yang Zhang [1]; Richard W. Carthew [3]; Randall T. Moon (corresponding author) [1] Inappropriate activation of downstream [...]

Research has been conducted on RNAi, gene silencing by double-stranded RNA. Results indicate that RNAi is established in Drosophila female germe line and that RNAi regulation and oogenesis translation control are mediated by similar mechanism.

Mutations in a gene called ebi were identified in screening for mutations that affect eye development. Genetic analysis found that ebi functions in EGFR pathways regulating aspects of gametogenesis and in imaginal disc development. The newly identified gene is quite homologous to proteins in plants, yeast and humans and is related structurally to Cdc4/Sel-10/Slimb. It has been shown that ebi is necessary in R7 development for down-regulating Ttk88 responding to epidermal growth factor (EGFR) signals. Mutations in ebi (ital) and Egfr (ital) give rise to similar phenotypes. They interact genetically, and ebi regulates EGFR receptor signaling pathways in Drosophila. The new gene does not have genetic interactions with other RTKs or with components of the canonical Ras/MAP kinase pathway.

Gene transcription repression is basic to nuclear hormone receptors. Cell-specific repression by nuclear receptors relates to levels of nuclear receptor corepressor (N-CoR) protein, based on recent experimentation. Aimed proteolysis of transcriptional coregulators has been found to be a path for cell-specific regulation of gene transcription.