Heart and Liver Defects and Reduced Transforming Growth Factor beta 2 Sensitivity in Transforming Growth Factor beta Type III Receptor-Deficient Embryos

• Published in: Molecular and cellular biology 2003-06, Vol.23 (12), p.4371-4385
• Main Authors: Stenvers, K L, Tursky, M L, Harder, K W, Kountouri, N, Amatayakul-Chantler, S, Grail, D, Small, C, Weinberg, R A, Sizeland, A M, Zhu, H
• Format: Article
• Language: English
• ISSN: 0270-7306
• DOI: 10.1128/MCB.23.12.4371-4385.2003

The type III transforming growth factor beta (TGF beta ) receptor (T beta RIII) binds both TGF beta and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of T beta RIII signaling in vivo is not known. In this study, we have sought to determine the role of T beta RIII during development. We identified the predominant expression sites of T beta RIII mRNA as liver and heart during midgestation and have disrupted the murine T beta RIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in T beta RIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that T beta RIII is required during murine somatic development. To assess the effects of the absence of T beta RIII on the function of its ligands, primary fibroblasts were generated from T beta RIII-null and wild-type embryos. Our results indicate that T beta RIII deficiency differentially affects the activities of TGF beta ligands. Notably, T beta RIII-null cells exhibited significantly reduced sensitivity to TGF beta 2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that T beta RIII is an important modulator of TGF beta 2 function in embryonic fibroblasts and that reduced sensitivity to TGF beta 2 may underlie aspects of the T beta RIII mutant phenotype.