Owen L. Coon Professor
RNAi and Gene Regulation
RNA has traditionally been thought of as a molecule that imparts information, structure or catalytic activities. Recently, a new role for RNA was discovered; it also regulates gene expression. This role, known as RNAi, mediates widespread defense against transposable elements and viruses, and also serves to regulate the expression of cellular protein-coding genes. The RNAs that participate in this process are 21 to 23 nucleotide fragments that are processed from double-stranded precursor molecules. Once formed, these siRNAs and microRNAs associate with cellular proteins and guide those proteins to complementary nucleic acids (chromosomal DNA or mRNA transcripts) in the cell. The complexes then effect a repression of the target nucleic acid. In the case of chromosomal DNA, the RNA-protein complex initiates the packaging of DNA into heterochromatin. In the case of mRNA, the complex initiates the destruction of the transcript or blocks its translation into a protein product. Our group studies the mechanism and function of this process in the model system Drosophila melanogaster. We combine genetics and biochemistry in Drosophila to understand its mechanistic principles.
The impact of RNAi has profoundly touched the fields of development and cell biology, functional genomics, human disease, and drug therapy. This is particularly seen with the small non-coding RNAs called microRNAs. This remarkable class of RNAs constitute 1% of the genes in the human genome, and they repress the expression of protein-coding genes by attenuating protein synthesis. Although it is difficult to estimate the extent of microRNA regulation, from 4 - 20% of protein-coding genes might be directly controlled by microRNAs. We are interested in understanding how microRNAs specifically inhibit their target genes and the biological consequences of this regulation. To this end, we discovered that microRNAs stimulate adult stem cells to divide continuously. Another function of microRNAs is to promote the differentiation of photoreceptor neurons. Our goal is to decipher the rules of microRNA regulation regarding target and biological specificity in diverse tissues of the body. The combined effects of microRNAs may affect the expression of many human genes, and misregulation of microRNAs appears to underlie complex disease phenomena such as cancer susceptibility and progression.
A Systematic Genetic Screen to Dissect the MicroRNA Pathway in Drosophila. Pressman S, Reinke CA, Wang X, and Carthew RW. G3. 2012 April 1;2(4):437-448.
Biological Robustness and the Role of MicroRNAs: A Network Perspective. Peláez N and Carthew RW. Current Topics in Developmental Biology. 2012;99:237-255.
Cadherin-Dependent Cell Morphology in an Epithelium: Constructing a Quantitative Dynamical Model. Gemp IM, Carthew RW, and Hilgenfeldt S. PLoS Computational Biology. 2011 July 21;7(7):e1002115.
Cargo sorting to lysosome-related organelles regulates siRNA-mediated gene silencing. Harris D, Kim K, Nakahara K, Vásquez-Doorman C, and Carthew RW. Journal of Cell Biology. 2011 July 11;194(1):77-87.
Loqs and R2D2 act sequentially in the siRNA pathway in Drosophila. Marques JT, Kim K, Wu PH, Alleyne TM, Jafari N, and Carthew RW. Nature Structural & Molecular Biology. 2010 January;17(1):24-30.
The Endo-siRNA Pathway Is Essential for Robust Development of the Drosophila Embryo. Lucchetta EM, Carthew RW, and Ismagilov RF. PLoS ONE. 2009 October 23;4(10):e7576.
Silencing by small RNAs is linked to endosomal trafficking. Lee YS, Pressman S, Andress AP, Kim K, White JL, Cassidy JJ, Li X, Lubell K, Lim DH, Cho IS, Nakahara K, Preall JB, Bellare P, Sontheimer EJ, and Carthew RW. Nature Cell Biology. 2009 September;11(9):1150-1156.
A MicroRNA Imparts Robustness against Environmental Fluctuation during Development. Li X, Cassidy JJ, Reinke CA, Fischboeck S, and Carthew RW. Cell. 2009 April 17;137(2):273-282.
Origins and Mechanisms of miRNAs and siRNAs. Carthew RW and Sontheimer EJ. Cell. 2009 February 20;136(4):642-655.
Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye. Hayashi T, Xu C, and Carthew RW. Development. 2008 August 15;135(16):2787-2796.
BMP Signaling Goes Posttranscriptional in a microRNA Sort of Way. Reinke CA and Carthew RW. Developmental Cell. 2008 August 12;15(2):174-175.
View all publications by Richard Carthew listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.