Great times for mouse genetics: getting ready for large-scale ENU-mutagenesis

Great times for mouse genetics: getting ready for large-scale ENU-mutagenesis Mammalian Genome 11, 471 (2000). DOI: 10.1007/s003350010091 Incorporating Mouse Genome © Springer-Verlag New York Inc. 2000 Great times for mouse genetics: getting ready for large-scale ENU-mutagenesis “The mouse needs no defense.” This was Salome Welch’s re- known genes. Around 1994 Christiane Nu ¨ sslein-Volhard and sponse seven years ago when at a meeting in Crete a famous Wolfgang Driever initiated large-scale ENU mutagenesis screens Drosophila geneticist argued that if one was interested in verte- in zebrafish. Within a few years more than 1000 mutants were brates, one might study the zebrafish, but certainly not the mouse. isolated, providing a tremendously valuable resource. Together with Although most readers of Mammalian Genome probably agree the pioneering studies with ENU mutagenesis in the mouse, the work with Salome, the arguments that were used against the mouse of Nu ¨ sslein-Volhard and Driever provided the proof-of-concept that deserve reconsideration. large-scale screens do not have to be limited to flies or worms. To study gene function in any organism, mutants are needed. Several studies of the feasibility of large-scale mutagenesis in Many mutants. Drosophila geneticists had used mutants as their the mouse are now under way in several countries. Germany has major tool to work out the principles of how the basic body plan allocated substantial funding to functional genomics of model or- of an organism is established. Chemical mutagenesis produced ganisms. An important component of this research program is the thousands of flies and hundreds of mutants with specific phenotypes large-scale mouse ENU mutagenesis project at the GSF-Research of interest. Making mutants with suppressor or enhancer screens was Center for Environment and Health (Munich). Similar projects are routine, and finding the mutated gene was not an obstacle. under way at the MRC Mammalian Genetics Unit (Harwell) and at The challenge in the mouse was to find appropriate strategies the Oak Ridge National Laboratories (Oak Ridge). Establishment for making and discovering mice with mutated genes and anoma- of several ENU mutagenesis centers in the US is anticipated. Japan lous phenotypes. Only a few thousand mouse mutants had been has funded an ENU screen, and similar efforts are under way in collected in the history of mouse genetics, and positional cloning Australia and Canada. An “Action Plan of Mouse Genomics” (Bat- remained challenging. The genetic map had modest resolution, and tey et al., Nat. Genet. 21, 73–75, 1999) has been published, with a physical map of the genome was not available. At the time of the the NIH as a major supporter for exploiting the mouse as a model meeting in Crete, Bernhard Herrmann had just cloned the Brachy- organism for studying the pathogenesis of human disease. ury gene and Sylvia Vidal, Philippe Gros, and Emil Skamene had Important discussions about the merits of ENU mutagenesis just cloned the BCG gene. Despite their success, the path from have occurred at meetings of the International Mammalian Ge- phenotype to gene remained daunting. Few thought that mouse nome Society in London, Ann Arbor, Garmisch Partenkirchen, St. genetics could ever be used in the systematic way to which Dro- Petersburg, and Philadelphia. To bring together those interested in sophila or worm geneticists were accustomed. promoting and evaluating ENU-mutagenesis, a workshop was held At the time of the Crete meeting, the increasing numbers of in Schloß Hohenkammer, Germany, in November 1998, after the th knockout and transgenic mice generated great enthusiasm among 12 International Mouse Genome Meeting in Garmisch Parten- mouse biologists. For the first time, systematic efforts could be kirchen and with the support of HUGO-Europe and the German imagined to engineer mutations in specific genes. Gene targeting Ministry of Research, Technology and Education (BMBF). was viewed as the future of mouse genetics. The enthusiasm was HUGO-Europe sponsored a follow-up workshop at Monterotondo high despite the difficulties in choosing a gene for study among the (Italy) in November 1999. 75,000—150,000 genes in the genome, finding the affected phe- The enthusiasm for large-scale mutagenesis is heralding a new notype in engineered mice, and scaling these efforts to the tens of era in mouse genetics. Continuing research on the development thousands of genes that need to be studied. and refinement of phenotyping methods is critical if we are to fully The world changed dramatically in the ensuing years. Micro- exploit the power of phenotype-based approaches to mouse muta- satellites, cosmids, BACs, YACs, and ESTs are widely available. genesis. Many of the contributions at the workshops at Schloß The sequence of the mouse genome is expected to be complete in Hohenkammer and Monterotondo, as well as many subsequent the next few years. It was increasingly realized that although the developments in the community, have been compiled in this spe- fly and the worm are essential for pathway dissection, there is no cial issue of Mammalian Genome. These papers evaluate the mer- substitute for a mammal as a disease model. No doubt that this had its of chemical mutagenesis and the status of projects to discover to be the mouse. But what about the mutants? mutant mice as new models of human disease. An important result Bill Russell and his colleagues at the Oak Ridge National of the Schloß Hohenkammer workshop was the realization that Laboratory had introduced chemical mutagenesis with ENU in the making the mutants, even at large scale, is just the beginning and mouse in the late seventies. Several groups subsequently estab- that dissecting and defining the phenotypes will yield the most lished efficient mutagenesis protocols. The discovery of induced exciting insights. What is now necessary is in-depth, detailed, and mutants by Vernon Bode, Bill Dove, Jean-Louis Gue ´net and others systematic phenotyping—from pathology to profiles of gene ex- demonstrated the feasibility of chemical mutagenesis based on pression. Coupled with advances in genomics that will speed the ENU. Gene Rinchik had even tried ‘saturation’ mutagenesis on an identification of underlying genes, the growing mouse mutant re- 11-cM interval around the albino locus. Despite these successes, it source is set to have a major impact on functional genomics for the was not evident that chemical mutagenesis could be a routine tool foreseeable future. for large-scale studies of mouse genetics. The discovery of the circadian rhythm mutant clock by Joe Rudi Balling, Munich Takahashi and its positional cloning just a few years later changed Steve Brown, Harwell this picture. What an interesting phenotype! It would have been Martin Hrabe de Angelis, Munich very hard to find the clock mutant via gene-targeting approaches. Monica Justice, Houston Moreover, Greg Barsh and Sabine Cordes had shown that ENU Joe Nadeau, Cleveland mutagenesis could be used effectively to discover new alleles of Jo Peters, Harwell Mammalian Genome Springer Journals

Great times for mouse genetics: getting ready for large-scale ENU-mutagenesis

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Copyright © 2000 by Springer-Verlag New York Inc.
Life Sciences; Cell Biology; Anatomy; Zoology
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