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Molecular and Cellular Biology, June 2003, p. 4371-4385, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4371-4385.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Heart and Liver Defects and Reduced Transforming Growth Factor ß2 Sensitivity in Transforming Growth Factor ß Type III Receptor-Deficient Embryos

Kaye L. Stenvers,1* Melinda L. Tursky,1 Kenneth W. Harder,1 Nicole Kountouri,1 Supavadee Amatayakul-Chantler,1 Dianne Grail,1 Clayton Small,2 Robert A. Weinberg,2 Andrew M. Sizeland,1 and Hong-Jian Zhu1

Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia,1 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Boston, Massachusetts 021422

Received 16 September 2002/ Returned for modification 11 November 2002/ Accepted 19 March 2003

The type III transforming growth factor ß (TGFß) receptor (TßRIII) binds both TGFß and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of TßRIII signaling in vivo is not known. In this study, we have sought to determine the role of TßRIII during development. We identified the predominant expression sites of TßRIII mRNA as liver and heart during midgestation and have disrupted the murine TßRIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in TßRIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that TßRIII is required during murine somatic development. To assess the effects of the absence of TßRIII on the function of its ligands, primary fibroblasts were generated from TßRIII-null and wild-type embryos. Our results indicate that TßRIII deficiency differentially affects the activities of TGFß ligands. Notably, TßRIII-null cells exhibited significantly reduced sensitivity to TGFß2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that TßRIII is an important modulator of TGFß2 function in embryonic fibroblasts and that reduced sensitivity to TGFß2 may underlie aspects of the TßRIII mutant phenotype.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, P.O. Box 2008, Royal Melbourne Hospital, VIC 3050, Australia. Phone: (61) 3-9341-3155. Fax: (61) 3-9341-3104. E-mail: Kaye.Stenvers{at}ludwig.edu.au.

Molecular and Cellular Biology, June 2003, p. 4371-4385, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4371-4385.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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