A genetic screen for modifiers of Delta1 dependent Notch signaling function in the mouse

The Notch signaling pathway is an evolutionary 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 seven mutant lines that exhibit a Dll1^lacZ/+-dependent phenotype. These mutant mouse lines provide excellent in vivo tools to study the role of Notch signaling in kidney and liver function, cholesterol and iron metabolism, in cell-fate decisions and during maturation of T cells in the immune system.

Key Words: Delta1, Notch signaling pathway, Notch1, genetic screen, modifier

Online ISS 1091-6490
Copyright 2008 by the Genetics Society of America
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