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Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to
M Weinstein1, S P Monga, Y Liu
1Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20878, USA.
Abstract:
Smads serve as intracellular mediators of transforming growth factor beta (TGF-beta) signaling. After phosphorylation by activated type I TGF-beta receptors, Smad proteins translocate to the nucleus, where they serve as transcription factors and increase or decrease expression of TGF-beta target genes. Mice lacking one copy each of Smad2 and Smad3 suffered midgestation lethality due to liver hypoplasia and anemia, suggesting essential dosage requirements of TGF-beta signal components. This is likely due to abnormal adhesive properties of the mutant hepatocytes, which may result from a decrease in the level of the beta1-integrin and abnormal processing and localization of E-cadherin. Culture of mutant livers in vitro revealed the existence of a parallel developmental pathway mediated by hepatocyte growth factor (HGF), which could rescue the mutant phenotype independent of Smad activation. These pathways merge at the beta1-integrin, the level of which was increased by HGF in the cultured mutant livers. HGF treatment reversed the defects in cell proliferation and hepatic architecture in the Smad2(+/-); Smad3(+/-) livers.
Insights
Transforming growth factor beta (TGF-beta) signaling is crucial for liver development. Hepatocyte growth factor (HGF) offers a parallel pathway to rescue TGF-beta pathway defects in Smad2/Smad3 deficient mice.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Biology
Background:
- Smad proteins are key intracellular mediators of transforming growth factor beta (TGF-beta) signaling.
- TGF-beta signaling regulates gene expression via nuclear translocation of phosphorylated Smads.
- Mice with deficiencies in Smad2 and Smad3 exhibit midgestation lethality due to liver hypoplasia and anemia.
Purpose of the Study:
- To investigate the role of Smad2 and Smad3 in liver development.
- To explore alternative developmental pathways that may compensate for TGF-beta signaling defects.
- To understand the interaction between TGF-beta and hepatocyte growth factor (HGF) pathways in liver development.
Main Methods:
- Generation of Smad2(+/-); Smad3(+/-) mice to study liver development.
- In vitro culture of mutant livers to assess rescue pathways.
- Analysis of beta1-integrin and E-cadherin levels and localization.
- Assessment of cell proliferation and hepatic architecture.
Main Results:
- Smad2/Smad3 deficiency leads to liver hypoplasia, anemia, and defects in hepatocyte adhesion.
- Abnormalities in beta1-integrin and E-cadherin are associated with the mutant phenotype.
- Hepatocyte growth factor (HGF) activates a parallel pathway that rescues the mutant phenotype.
- HGF increases beta1-integrin levels, restoring cell proliferation and hepatic architecture.
Conclusions:
- TGF-beta signaling, mediated by Smad2 and Smad3, is essential for normal liver development.
- HGF can activate an alternative pathway that compensates for Smad deficiency.
- The beta1-integrin serves as a convergence point for both TGF-beta and HGF signaling pathways in liver development.