Originally published as Genetics Published Articles Ahead of Print on December 18, 2006.

Genetics, Vol. 175, 1451-1463, March 2007, Copyright © 2007
doi:10.1534/genetics.106.067298

A Genetic Screen for Modifiers of the Delta1-Dependent Notch Signaling Function in the Mouse

Isabel Rubio-Aliaga^*, Dian Soewarto^*,1, Sibylle Wagner^*, Matthias Klaften^*, Helmut Fuchs^*, Svetoslav Kalaydjiev, Dirk H. Busch, Martina Klempt, Birgit Rathkolb, Eckhard Wolf, Koichiro Abe^*,2, Stefan Zeiser, Gerhard K. H. Przemeck^*, Johannes Beckers^* and Martin Hrabé de Angelis^*,3

^* Institute of Experimental Genetics, GSF Research Center for Environment and Health, 85764 Neuherberg, Germany, Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany, Institute of Molecular Animal Breeding, Gene Center, University of Munich, 81377 Munich, Germany, Institute of Biomathematics and Biometry, GSF Research Center for Environment and Health, 85764 Neuherberg, Germany

³ Corresponding author: Institute of Experimental Genetics, GSF Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
E-mail: hrabe{at}gsf.de

The Notch signaling pathway is an evolutionarily conserved transduction pathway involved in embryonic patterning and regulation of cell fates during development. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, which are also involved in distinct human diseases. Delta1 is one of the known ligands of the Notch receptors. Mice homozygous for a loss-of-function allele of the Delta1 gene Dll1^lacZ/lacZ die during embryonic development. Here, we present the results of two phenotype-driven modifier screens. Heterozygous Dll1^lacZ knockout animals were crossed with ENU-mutagenized mice and screened for dysmorphological, clinical chemical, and immunological variants that are dependent on the Delta1 loss-of-function allele. First, we show that mutagenized heterozygous Dll1^lacZ offspring have reduced body weight and altered specific clinical chemical parameters, including changes in metabolites and electrolytes relevant for kidney function. In our mutagenesis screen we have successfully generated 35 new mutant lines. Of major interest are 7 mutant lines that exhibit a Dll1^lacZ/+-dependent phenotype. These mutant mouse lines provide excellent in vivo tools for studying the role of Notch signaling in kidney and liver function, cholesterol and iron metabolism, cell-fate decisions, and during maturation of T cells in the immune system.

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Genetics 2007 175: NP. [Full Text]  

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