Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner.
Tbx1 is a T-box transcription factor implicated in DiGeorge syndrome. The molecular function of Tbx1 is unclear although it can transactivate reporters with T-box binding elements. We discovered that Tbx1 binds Smad1 and suppresses the Bmp4/Smad1 signaling. Tbx1 interferes with Smad1 to Smad4 binding, and a mutation of Tbx1 that abolishes transactivation, does not affect Smad1 binding nor does affect the ability to suppress Smad1 activity. In addition, a disease-associated mutation of TBX1 that does not prevent transactivation, prevents the TBX1-SMAD1 interaction. Expression of Tbx1 in transgenic mice generates phenotypes similar to those associated with loss of a Bmp receptor. One phenotype could be rescued by transgenic Smad1 expression. Our data indicate that Tbx1 interferes with Bmp/Smad1 signaling and provide strong evidence that a T-box transcription factor has functions unrelated to transactivation.
Fulcoli
F Gabriella
FG
Telethon Institute of Genetics and Medicine, Naples, Italy.
Huynh
Tuong
T
Scambler
Peter J
PJ
Baldini
Antonio
A
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051898:Smad1 Protein / Q000096:biosynthesis*; D051901:Smad4 Protein / Q000096:biosynthesis; D020825:T-Box Domain Proteins / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse