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Targeted disruption of the Tab1 gene causes embryonic lethality and defects in cardiovascular and lung morphogenesis
Yoshihiro Komatsu1, Hiroshi Shibuya, Naoki Takeda
1Center for Animal Resources and Development, Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Abstract:
The transforming growth factor-beta (TGF-beta) superfamily consists of a group of secreted signaling molecules that perform important roles in the regulation of cell growth and differentiation. TGF-beta activated kinase-1 binding protein-1 (TAB1) was identified as a molecule that activates TGF-beta activated kinase-1 (TAK1). Recent studies have revealed that the TAB1-TAK1 interaction plays an important role in signal transduction in vitro, but little is known about the role of these molecules in vivo. To investigate the role of TAB1 during development, we cloned the murine Tab1 gene and disrupted it by homologous recombination. Homozygous Tab1 mutant mice died, exhibiting a bloated appearance with extensive edema and hemorrhage at the late stages of gestation. By histological examinations, it was revealed that mutant embryos exhibited cardiovascular and lung dysmorphogenesis. Tab1 mutant embryonic fibroblast cells displayed drastically reduced TAK1 kinase activities and decreased sensitivity to TGF-beta stimulation. These results indicate a possibility that TAB1 plays an important role in mammalian embryogenesis and is required for TAK1 activation in TGF-beta signaling.
Insights
Transforming growth factor-beta (TGF-beta) binding protein-1 (TAB1) is essential for mammalian embryogenesis. Disruption of the Tab1 gene in mice leads to embryonic lethality due to cardiovascular and lung developmental defects.
Area of Science:
- Cellular biology
- Developmental biology
- Molecular signaling
Background:
- The transforming growth factor-beta (TGF-beta) superfamily regulates cell growth and differentiation.
- TGF-beta activated kinase-1 binding protein-1 (TAB1) activates TGF-beta activated kinase-1 (TAK1).
- The in vivo role of the TAB1-TAK1 interaction in development is largely unknown.
Purpose of the Study:
- To investigate the role of TAB1 in mammalian development.
- To characterize the function of TAB1 in vivo using a gene knockout model.
Main Methods:
- Cloning of the murine Tab1 gene.
- Gene disruption via homologous recombination in mice.
- Histological examination of mutant embryos.
- Analysis of TAK1 kinase activity in Tab1 mutant cells.
Main Results:
- Homozygous Tab1 mutant mice exhibited embryonic lethality with severe edema and hemorrhage.
- Mutant embryos displayed significant cardiovascular and lung dysmorphogenesis.
- Tab1 mutant fibroblasts showed reduced TAK1 kinase activity and impaired TGF-beta signaling response.
Conclusions:
- TAB1 is crucial for mammalian embryogenesis.
- TAB1 is required for proper TAK1 activation within the TGF-beta signaling pathway.
- The TAB1-TAK1 axis plays a vital role in embryonic development, particularly in cardiovascular and lung formation.