Reagents Developed for Genomic Engineering of Mouse Models for Better Insights into Human Disease

The ability to specifically target and modify genes in the mouse allows researchers to use this small rodent to evaluate how specific genes contribute to human disease. A common method used to make genetic changes in mice and cells is called site-specific recombination, where two DNA strands are exchanged. The two strands may contain very different sequences, but are designated at their ends by specific target sequences that are not typically found elsewhere in the genome. A protein, called a recombinase, cuts the DNA at its target sites and rearranges it. Scientists use this technique to exchange a naturally occurring DNA sequence for an altered or deleted gene to gain insight into the gene's normal function or how it contributes to disease.

Currently there are a few systems available to create genetic mutations in mice, including the recombinases FLP and Cre. These proteins are very efficient genetic modifiers and specifically target their appropriate sequences. They can also be switched on or off at precise times, or within specific tissues, to make carefully regulated genetic changes. However, the small number of available methods that can be used together to mutate genes limits the complexity of the modifications that can be generated. For example, it would be informative to independently regulate the temporal and tissue-specific expression of genes with overlapping functions to understand their individual and combined effects.

Dre works similarly to the currently popular recombinase Cre, with an important exception: Dre recognizes a distinct target sequence and only recombines DNA around its target sequence, even if the target sequence for Cre is present. The ability of the related proteins, Cre and Dre to differentiate their own target sequences indicates that Dre can be used in combination with Cre, and other recombinases, to produce more sophisticated mouse models. This should facilitate the analysis of complex gene interactions and how they function in disease.

This technologic development also highlights the progress that might be made through open reagent sharing within the scientific community. The discovery of Dre recombinase was originally reported by Drs. Brian Sauer and Jeffrey McDermott at the Stowers Institute for Medical Research (Kansas City, MO, USa). The Institute holds an intellectual patent for the system that allows it to be shared openly for noncommercial purposes and evaluates requests on a case-by-case basis for its use by for-profit institutions.

The researchers involved in the study included Dr. Konstantinos Anastassiadis and Dr. Jun Fu from the Center for Regenerative Therapies Dresden (Germany); BioInnovationsZentrum Technische Universitaet Dresden (Germany); and Dr. Christoph Patsch, from the Institute of Reconstructive Neurobiology, University of Bonn (Germany).

The study was published in the September/October 2009 issue of the new research journal, Disease Models & Mechanisms (DMM).

Related Links:
Stowers Institute for Medical Research
Center for Regenerative Therapies Dresden
BioInnovationsZentrum Technische Universitaet Dresden
Institute of Reconstructive Neurobiology, University of Bonn