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Fgf3-Fgf4-cis: A new mouse line for studying Fgf functions during mouse development
Matthew J Anderson1, Eileen Southon2, Lino Tessarollo2
1Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, 21702, Maryland.
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.
Insights
Researchers developed a new mouse model to study redundant fibroblast growth factor (FGF) gene functions. This model overcomes challenges in studying Fgf3 and Fgf4, enabling deeper insights into FGF signaling in development and disease.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Fibroblast growth factor (FGF) signaling is essential for embryonic development and implicated in various diseases.
- Genetic studies in mice have revealed functional redundancy among FGF ligands.
- Studying redundancy between closely located genes like Fgf3 and Fgf4 is challenging due to infrequent genetic recombination.
Purpose of the Study:
- To develop a novel mouse model enabling the study of functional redundancy between Fgf3 and Fgf4.
- To overcome the limitations of studying closely linked genes in cis.
Main Methods:
- Retargeting of Fgf3 and Fgf4 genes in cis within an F1 embryonic stem cell line.
- Generation of an Fgf3 null allele and a conditional Fgf4 allele (Fgf3(Δ)-Fgf4(flox)-cis).
- Confirmation of cis targeting using allele-specific single-nucleotide polymorphisms.
Main Results:
- Successful generation of the Fgf3(Δ)-Fgf4(flox)-cis mouse line.
- Demonstrated increased severity of caudal axis extension defects when both Fgf4 and Fgf3 are inactivated.
- Validated the utility of the new mouse line for studying gene redundancy.
Conclusions:
- The Fgf3(Δ)-Fgf4(flox)-cis mouse line provides a powerful tool for investigating FGF gene redundancy.
- This model will facilitate research into the roles of Fgf3 and Fgf4 in various developmental processes and disease contexts.
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