title: A genetic screen for modifiers of the delta1-dependent notch signaling function in the mouse.
abstract: 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.
authors.affiliation: Institute of Experimental Genetics, GSF Research Center for Environment and Health, 85764 Neuherberg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rubio-Aliaga
authors.forename: Dian
authors.initials: D
authors.lastname: Soewarto
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wagner
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Martina
authors.initials: M
authors.lastname: Klempt
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeiser
authors.forename: Gerhard K H
authors.initials: GK
authors.lastname: Przemeck
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
mesh_terms: D000483:Alleles; D000818:Animals; D001774:Blood Chemical Analysis; D001824:Body Constitution / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D001837:Body Weights and Measures; D003433:Crosses, Genetic; D017931:DNA Primers; D005820:Genetic Testing; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice / Q000235:genetics*; D018345:Mice, Knockout; D016296:Mutagenesis; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D017931:DNA Primers; C511877:Dll3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins