miRNA Models of Neurodegenerative Disease   
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  miRNA Models of Neurodegenerative Disease  
  Lab Location: #8-06
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  miRNA Models of Neurodegenerative Disease

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.