Heart and Liver Defects and Reduced Transforming Growth Factor β2 Sensitivity in Transforming Growth Factor β Type III Receptor-Deficient Embryos

Autor: Dianne Grail, Hong-Jian Zhu, Clayton G. Small, Nicole Kountouri, Kenneth W. Harder, Robert A. Weinberg, Supavadee Amatayakul-Chantler, Kaye L. Stenvers, Andrew M. Sizeland, Melinda L. Tursky
Rok vydání: 2003
Předmět:
Genetically modified mouse
Time Factors
Immunoblotting
Biology
Ligands
Sensitivity and Specificity
Inhibitory Concentration 50
Mice
chemistry.chemical_compound
Genes
Reporter
Transforming Growth Factor beta
TGF beta signaling pathway
Mammalian Genetic Models with Minimal or Complex Phenotypes
Animals
RNA
Messenger
Receptor
Molecular Biology
Cell Nucleus
Mice
Knockout
Recombination
Genetic
Reporter gene
Dose-Response Relationship
Drug
Models
Genetic
Reverse Transcriptase Polymerase Chain Reaction
Myocardium
Heart
Cell Biology
Transforming growth factor beta
Fibroblasts
Blotting
Northern
Flow Cytometry
Immunohistochemistry
Molecular biology
Cell biology
Blotting
Southern
Phenotype
Liver
Microscopy
Fluorescence
chemistry
biology.protein
Proteoglycans
Growth inhibition
Signal transduction
Receptors
Transforming Growth Factor beta
Signal Transduction
Transforming growth factor
Zdroj: Molecular and Cellular Biology. 23:4371-4385
ISSN: 1098-5549
Popis: The type III transforming growth factor beta (TGFbeta) receptor (TbetaRIII) binds both TGFbeta and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of TbetaRIII signaling in vivo is not known. In this study, we have sought to determine the role of TbetaRIII during development. We identified the predominant expression sites of TbetaRIII mRNA as liver and heart during midgestation and have disrupted the murine TbetaRIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in TbetaRIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that TbetaRIII is required during murine somatic development. To assess the effects of the absence of TbetaRIII on the function of its ligands, primary fibroblasts were generated from TbetaRIII-null and wild-type embryos. Our results indicate that TbetaRIII deficiency differentially affects the activities of TGFbeta ligands. Notably, TbetaRIII-null cells exhibited significantly reduced sensitivity to TGFbeta2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that TbetaRIII is an important modulator of TGFbeta2 function in embryonic fibroblasts and that reduced sensitivity to TGFbeta2 may underlie aspects of the TbetaRIII mutant phenotype.
Databáze: OpenAIRE
Externí odkaz: