Peptide growth factors, such as the Transforming Growth Factor beta (TGFbeta) family, play central roles in morphogenesis and organogenesis. The narrowly defined vertebrate TGFbeta family is composed of at least three 25 kilodalton homodimeric proteins, TGFbeta1, TGFbeta2, and TGFbeta3. TGFbeta1 and TGFbeta 3 share identical ligand binding and biological activities while TGFbeta2 has a unique requirement for the Type III TGFbeta receptor (TBRIII) and distinct biological activities. We have recently demonstrated a requirement for TBRIII in TGFbeta-mediated epithelial-mesenchymal cell transformation that occurs in the atrioventricular (AV) cushion of the developing heart. We are testing the hypothesis that a unique receptor signal transduction complex is responsible for AV cushion transformation. Since current models of TGFbeta signal transduction presuppose a requirement for a Type I receptor (TBRI) in the signal transduction complex, initial experiments will determine if a Type I receptor (TBRI) is a component of the receptor complex in the AV cushion. Specifically, we will determine whether the ALK2 or ALK5 TBRI is required for transformation. This will be determined both by misexpression of constituitively active ALK2 and ALK5 and antisense constructs. A well described pathway for downstream signal transduction from TGFbeta receptors includes the Smads family of transcription factors. We will test the hypothesis that specific Smads are necessary for AV cushion transformation by , determining if dominate negative inhibitors of Smads or constitutively active Smads alter transformation in AV cushion explants and ventricular explants. Preliminary data in our laboratory suggests a role for the ALK2, and not ALK5, in transformation. Therefore we will test the hypothesis that ALK2 associates with TBRIII to mediate transformation by immunoprecipitation of the TGFbeta receptor complex and identification of ALK2 and ALK5. We also will immunolocalize TBRI and TBRIII on both chick embryonic fibroblasts and AV cushion endothelial cells to determine whether they associate after the addition of TGFbeta. These experiments are part of a concerted strategy to determine whether TBRIII requires a TBRI and downstream Smad signaling. Our long-term goal to understand the role of TGFbeta in cushion transformation and the genesis of congenital heart defects due to abnormal cushion transformation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cell Development and Function Integrated Review Group (CDF)
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Schramm, Charlene A
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Vanderbilt University Medical Center
Schools of Medicine
United States
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