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Published on: August 23, 2014
High expression of Pitx-2 in the ICAT-deficient metanephros leads to developmental arrest
Yoshimi Hasegawa1, Akiko Iizuka-Kogo, Tetsu Akiyama
1Department of Anatomy I, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
Abstract:
ICAT (Inhibitor of β-catenin and T cell factor) inhibits the interaction between β-catenin and TCF/LEF transcription factor and serves as a negative regulator of Wnt signaling. In a subset of ICAT knockout mice, significant delay in the ureteric bud branching and renal agenesis are observed. In order to examine the process of this developmental defect, molecular changes were analyzed in fetal ICAT-/- kidneys with a focus on Wnt-signaling associated factors. The protein level of active β-catenin was elevated in ICAT-/- kidneys. DNA microarray and immunohistochemical analyses revealed that the expression of a Wnt target gene Pitx-2 was enhanced in ICAT-/- kidneys. There was no genotypic difference in the expression level of another Wnt target gene, c-Ret. These results suggest that the enhancement of Pitx-2 expression induced by activated Wnt signaling leads to delays in ureteric bud branching and subsequent renal agenesis. In the ICAT-/- kidneys which developed to E18.5 without any apparent defect, renal glomeruli, convoluted tubules and collecting ducts were decreased in density and showed abnormal structure. ICAT may be required for various developmental stages during renal development.
Insights
Inhibitor of β-catenin and T cell factor (ICAT) deficiency delays kidney development by enhancing Wnt signaling, leading to ureteric bud branching defects and renal agenesis in mice.
Area of Science:
- Developmental biology
- Molecular biology
- Genetics
Background:
- The Wnt signaling pathway is crucial for embryonic development.
- β-catenin and TCF/LEF transcription factors are key components of Wnt signaling.
- Inhibitor of β-catenin and T cell factor (ICAT) negatively regulates Wnt signaling.
Purpose of the Study:
- To investigate the role of ICAT in renal development.
- To elucidate the molecular mechanisms underlying renal developmental defects in ICAT knockout mice.
Main Methods:
- Analysis of molecular changes in fetal ICAT-/- kidneys.
- Focus on Wnt-signaling associated factors.
- DNA microarray and immunohistochemical analyses.
Main Results:
- Elevated protein levels of active β-catenin in ICAT-/- kidneys.
- Enhanced expression of the Wnt target gene Pitx-2 in ICAT-/- kidneys.
- No significant difference in c-Ret expression between genotypes.
Conclusions:
- Enhanced Pitx-2 expression due to activated Wnt signaling contributes to delayed ureteric bud branching and renal agenesis.
- ICAT is essential for normal renal development at various stages.
