title: Fgf3-Fgf4-cis: A new mouse line for studying Fgf functions during mouse development.
abstract: The fibroblast growth factor (FGF) family consists of 22 ligands in mice and humans. FGF signaling is vital for embryogenesis and, when dysregulated, can cause disease. Loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. Such analysis has revealed that multiple Fgfs sometimes function redundantly. Exploring such redundancy between Fgf3 and Fgf4 is currently impossible because both genes are located on chromosome 7, about 18.5 kb apart, making the frequency of interallelic cross-over between existing mutant alleles too infrequent to be practicable. Therefore, we retargeted Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele, subject to Cre inactivation. To increase the frequency of cis targeting, we used an F1 embryonic stem cell line that contained 129/SvJae (129) and C57BL/6J (B6) chromosomes and targeting constructs isogenic to the 129 chromosome. We confirmed cis targeting by assaying for B6/129 allele-specific single-nucleotide polymorphisms. We demonstrated the utility of the Fgf3(Δ)-Fgf4(flox)-cis mouse line by showing that the caudal axis extension defects found in the Fgf3 mutants worsen when Fgf4 is also inactivated. This Fgf3(Δ)-Fgf4(flox)-cis line will be useful to study redundancy of these genes in a variety of tissues and stages in development.
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, 21702, Maryland.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Anderson
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, 21702, Maryland.
authors.forename: Eileen
authors.initials: E
authors.lastname: Southon
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, Frederick, 21702, Maryland.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, 21702, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells; D051518:Fibroblast Growth Factor 3 / Q000235:genetics*; D051519:Fibroblast Growth Factor 4 / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C489197:Fgf3 protein, mouse; C496446:Fgf4 protein, mouse; D051518:Fibroblast Growth Factor 3; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors
keywords: FGF; FGF3; FGF4; axis extension; genetic redundancy; mouse development; presomitic mesoderm