As published in Genes & Development, researchers from the University of Virginia have developed a new and powerful transgenic mouse model system. This system allows scientists to introduce a foreign gene into the mouse and turn this gene on and off at will through a simple dietary change. The paper details the careful genetic manipulation behind this work and the eye-catching results – mice that change color when a special supplement is added to their drinking water, and revert back to their original color once the supplement is removed!
Dr. Scrable and colleagues genetically engineered the bacterial lac operon for use as an inducible gene regulatory system in the mouse. The lac regulatory system in the mouse provides tight, reversible control of specific gene expression – a tool that will be of wide interest to those who model human disease and development.
The lac operon in E. coli consists of a set of regulatory elements and structural genes whose products enable the bacterial cell to metabolize lactose. In the absence of lactose, lac structural genes are not transcribed because the lac repressor protein is bound to the lac operator, thereby preventing RNA polymerase from initiating transcription. When the lactose analog IPTG is present, the lac repressor protein binds IPTG and undergoes a conformational change that decreases its affinity for the lac operator and allows for transcription to occur. Dr. Scrable and colleagues have spent the past four years adapting this bacterial operon for use as a gene regulatory system in the mouse.
Dr. Scrable and colleagues manipulated the DNA sequence and gene structure of the lac repressor protein so that it is expressed ubiquitously in the mouse. By strategically integrating lac operator sequences within the promoter of a reporter gene, tyrosinase, Dr. Scrable and colleagues generated a mouse strain that expresses tyrosinase only in the presence of IPTG. As tyrosinase encodes an enzyme necessary for coat color, their experiments had startling results.
Dr. Scrable and colleagues demonstrated that tyrosinase is repressed in the absence of IPTG, causing mice to develop as purely white albinos. When IPTG is added to the drinking water, tyrosinase is activated and the coat color changes to brown. However, once IPTG is depleted, tyrosinase is again turned off and the albino phenotype returns. Interestingly, these effects occur in both adult mice and in embryos that are exposed to IPTG via the mother’s drinking water.
The IPTG inducible system developed by Dr. Scrable and colleagues represents a marked advance in mammalian model systems. Although further analysis is needed before all features of the system are fully realized, Dr. Alea Mills, an expert in this field, remarked that this system "appears to fulfill the criteria for an optimal inducible system." As the mouse is the most widely used experimental system to model human disease and development, this revolutionary new system will greatly broaden the range of biological questions that scientists can address experimentally.
The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.
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