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Published on: March 16, 2022
Generation of mice carrying a knockout-first and conditional-ready allele of transforming growth factor beta2 gene
A S Ishtiaq Ahmed1, Gracelyn C Bose, Li Huang
1Department of Pediatrics, Program in Developmental Biology and Neonatal Medicine, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract:
Transforming growth factor beta2 (TGFβ2) is a multifunctional protein which is expressed in several embryonic and adult organs. TGFB2 mutations can cause Loeys Dietz syndrome, and its dysregulation is involved in cardiovascular, skeletal, ocular, and neuromuscular diseases, osteoarthritis, tissue fibrosis, and various forms of cancer. TGFβ2 is involved in cell growth, apoptosis, cell migration, cell differentiation, cell-matrix remodeling, epithelial-mesenchymal transition, and wound healing in a highly context-dependent and tissue-specific manner. Tgfb2(-/-) mice die perinatally from congenital heart disease, precluding functional studies in adults. Here, we have generated mice harboring Tgfb2(βgeo) (knockout-first lacZ-tagged insertion) gene-trap allele and Tgfb2(flox) conditional allele. Tgfb2(βgeo/βgeo) or Tgfb2(βgeo/-) mice died at perinatal stage from the same congenital heart defects as Tgfb2(-/-) mice. β-galactosidase staining successfully detected Tgfb2 expression in the heterozygous Tgfb2(βgeo) fetal tissue sections. Tgfb2(flox) mice were produced by crossing the Tgfb2(+/βgeo) mice with the FLPeR mice. Tgfb2(flox/-) mice were viable. Tgfb2 conditional knockout (Tgfb2(cko/-) ) fetuses were generated by crossing of Tgfb2(flox/-) mice with Tgfb2(+/-) ; EIIaCre mice. Systemic Tgfb2(cko/-) embryos developed cardiac defects which resembled the Tgfb2(βgeo/βgeo) , Tgfb2(βgeo/-) , and Tgfb2(-/-) fetuses. In conclusion, Tgfb2(βgeo) and Tgfb2(flox) mice are novel mouse strains which will be useful for investigating the tissue specific expression and function of TGFβ2 in embryonic development, adult organs, and disease pathogenesis and cancer. genesis
Insights
New mouse models for transforming growth factor beta2 (TGFβ2) allow researchers to study its role in development and disease. These models enable investigation into TGFβ2
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Transforming growth factor beta2 (TGFβ2) is crucial for development and implicated in various diseases.
- TGFβ2 dysregulation is linked to cardiovascular, skeletal, ocular, and neuromuscular disorders, fibrosis, and cancer.
- Existing TGFβ2 knockout mice die perinatally, limiting adult functional studies.
Purpose of the Study:
- To generate novel mouse models for studying the tissue-specific functions of TGFβ2.
- To enable investigation of TGFβ2's role in embryonic development and adult diseases.
- To overcome limitations of previous knockout models for TGFβ2 research.
Main Methods:
- Generation of Tgfb2(βgeo) (gene-trap) and Tgfb2(flox) (conditional) alleles.
- Analysis of Tgfb2(βgeo/βgeo) and Tgfb2(βgeo/-) mice for developmental defects.
- Creation and analysis of Tgfb2 conditional knockout (Tgfb2(cko/-)) mice.
Main Results:
- Tgfb2(βgeo/βgeo) and Tgfb2(βgeo/-) mice exhibited perinatal lethality due to congenital heart defects.
- β-galactosidase staining confirmed Tgfb2 expression patterns in fetal tissues.
- Tgfb2(flox/-) mice were viable, and Tgfb2(cko/-) embryos showed cardiac defects similar to constitutive knockouts.
Conclusions:
- The novel Tgfb2(βgeo) and Tgfb2(flox) mouse strains are valuable tools for studying TGFβ2.
- These models facilitate research into TGFβ2's function during embryonic development and in adult organ systems.
- The models will aid in understanding TGFβ2's role in disease pathogenesis, including cancer.
