Stephen COHEN   
                       
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  Stephen COHEN  
  Lab Location: #8-06

email:
scohen@imcb.a-star.edu.sg
tel:65869725
 
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  Key Publications  
 

Zhang, W., Hietakangas,V., Wee, S.,  Lim, R.  Gunaratne, J., and Cohen, S.M.  (2013) ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation.
Genes Dev in press

Herranz, H., Hong, X., Nguyen T.H., Voorhoeve, P.M. and Cohen, S.M.  (2012) Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model.
Genes Dev 26, 1602-1611.

Herranz, H., Hong, X., and Cohen, S.M.  (2012)
Mutual repression by bantam miRNA and Capicua links the EGFR/MAPK and Hippo pathways in growth control. Current Biol. 22, 651-657 Doi: 10.1016/j.cub.2012.02.050 published online 22 March 2012

Varghese, J., Lim, S., and SM Cohen (2010)
Drosophila miR-14 regulates insulin production and metabolism through its target sugarbabe.
Genes Dev.
24: 2748-2753.

Herranz, H. and SM Cohen (2010)
microRNAs and gene regulatory networks: managing the impact of noise in biological systems.
Genes Dev
24, 1339-1344

Hilgers,V., Bushati, N., & Cohen, SM (2010)
Drosophila microRNAs 263a/b confer robustness during development by protecting nascent sense organs from apoptosis.
PLoS Biology
15:8(6):
e1000396

Hong, X., Hammell, M. Ambros, V and Cohen, S.M. (2009)
Identification of microRNA targets by immunopurification of Ago1 RNPs: selection for a distinct class of targets.
PNAS 106, 15085-90.

Bushati, N., Stark, A., Brennecke, J., and Cohen, S.M. (2008)
Temporal reciprocity of microRNAs and their targets during the maternal to zygotic transition in Drosophila.
Current Biology
18, 501-506.

J Karres, V Hilgers, I Carrera, J Treisman & SM Cohen (2007)
The conserved microRNA miR-8 tunes Atrophin levels to prevent neurodegeneration in Drosophila.
Cell
131, 136–145.

Teleman, A.A., Maitra S. & Cohen S.M. (2006)
Drosophila lacking microRNA miR-278 are defective in energy homeostasis.
Genes Dev.20,417-422.

BJ Thompson & SM Cohen  (2006)
The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila.
Cell.126, 767-774.

Stark, A., Brennecke, J., Bushati, N. Russell, R.B. & Cohen, S.M. (2005)
Animal microRNAs confer robustness to gene expression and have a significant impact on 3’UTR evolution.
Cell 123,1133-1146.

Brennecke, J., Hipfner, D.R. Stark, A., Russell, R & Cohen, S.M. (2003)
bantam encodes a developmentally regulated microRNAthatcontrols cell proliferation and regulates the pro-apoptotic gene hid in Drosophila.
Cell 113: 25-36.

 

 

 

 
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  Stephen COHEN


Stephen Cohen received his PhD from Princeton University. He did post-doctoral work at the Whitehead Institute at MIT and later at the Max Planck Institute in Tübigen Germany, where he began to work on Drosophila developmental genetics. He was a Howard Hughes Medical Institute Assistant Investigator at Baylor College of Medicine in Houston Texas, before moving to the European Molecular Biology Laboratory in 1993. In 1996, he became Head of the Developmental Biology Unit at EMBL and was elected as a member of the European Molecular Biology Organization. In 2007 he moved to Singapore to take a position as Executive Director of the Temasek Life Sciences Laboratory. In 2008 he was elected as a Fellow of the Royal Society of London. He serves on the editorial boards of Cell, Genes and Development, Developmental Cell and is an Editor of Developmental Biology. He also serves on the scientific advisory boards of several research institutes in Europe and Asia. His research interests have included appendage development and pattern formation, morphogen gradients, growth control and metabolism. More recently the lab is concentrating on the functions of microRNAs in development and homeostasis. He joined IMCB as Research Director in July 2010.

     
  miRNA
 


Over the years our lab has studied pattern formation and growth control. We have used the fly as a model because of its unparalleled flexibility for genetic manipulation. By focusing on appendage development in a simple system, we were able to provide insights into processes fundamental to animal development. Among these was the identification of genes required for appendage development (now called Dlx genes) and the finding that compartment boundaries serve as patterning centers by producing gradients of secreted signaling proteins. These morphogenetic gradients instruct cells about their fate as a function of their position. We have also studied how morphogen gradients contribute to size control. This interest set the stage for our current work, because we identified microRNA genes involved in control of tissue growth.

For several years the lab has focused on understanding biological functions of microRNAs. We have found that microRNAs are key regulators of tissue growth, cell death, metabolism, a range of biological processes relevant to development and disease. Our approach combines genetic analysis, to understand the biological process affected by the microRNA, with development of computational and biochemical tools to help identify the target genes that microRNAs regulate.

One key finding was reciprocity between microRNAs and their targets in terms of spatial and temporal expression. This led to the realization that many microRNAs act to reduce target expression to inconsequential levels, a process that we call ‘noise reduction’. The biological role of this class of miRNAs is to ensure robustness of development by ensuring that transcriptional noise is kept in check.

We have also provided evidence for a second category of microRNA action: setting a precise level of target expression. In such cases the microRNA and its target are co-expressed and the microRNA contributes to defining an optimal range of target expression levels. Examples include regulation of Atrophin by miR-8. Failure of this regulation leads to a neurodegenerative disorder. Another example involves control of insulin production by miR-14 A third mode of miRNA action involves microRNA-based feedback regulatory loops. In such cases the microRNAs can be involved in feedback regulation with a transcription factor to form a developmental switch. microRNA-dependent feedback regulatory circuits are likely to be important in disease, given their potential role in homeostatic control.

We have undertaken a long-term project to knock-out all fly microRNA genes in order to learn more about their functions. To date we have generated mutants for >90% of them and are beginning to find roles in a range of processes, including cell proliferation, metabolism, lifespan. Other mutants point to functions in the brain, which manifest themselves as behavioral defects and neurodegeneration.

At the cellular level much is similar between flies and mammals. This allows the possibility of using fly models for discovery of biological mechanisms relevant to all animals. We hope to exploit the potential for discovery in the fly as a means to accelerate our understanding of the roles of microRNAs in disease-relevant areas of biology.

     

Figure Legend:

Drosophila miR-14 acts in insulin-producing neurosecretory cells in the adult brain to control metabolism. The image shows a fly brain expressing a lacZ reporter (red) to visualize miR-14 expression, and membrane-tethered GFP (green) to label the cell bodies and axonal projections of the insulin-producing neurons. Insulin mRNA levels are controlled in these cells by the microRNA miR-14 through regulation of its direct target, sugarbabe. Misregulation of sugarbabe in flies lacking miR-14 produces metabolic defects due to abnormal insulin levels.