Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract.
Dysmorphogenesis of the cardiac outflow tract (OFT) causes many congenital heart defects, including those associated with DiGeorge syndrome. Genetic manipulation in the mouse and mutational analysis in patients have shown that Tbx1, a T-box transcription factor, has a key role in the pathogenesis of this syndrome. Here, we have dissected Tbx1 function during OFT development using genetically modified mice and tissue-specific deletion, and have defined a dual role for this protein in OFT morphogenesis. We show that Tbx1 regulates cell contribution to the OFT by supporting cell proliferation in the secondary heart field, a source of cells fated to the OFT. This process might be regulated in part by Fgf10, which we show for the first time to be a direct target of Tbx1 in vitro. We also show that Tbx1 expression is required in cells expressing Nkx2.5 for the formation of the aorto-pulmonary septum, which divides the aorta from the main pulmonary artery. These results explain why aortic arch patterning defects and OFT defects can occur independently in individuals with DiGeorge syndrome. Furthermore, our data link, for the first time, the function of the secondary heart field to congenital heart disease.
Xu
Huansheng
H
Program in Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Morishima
Masae
M
Wylie
John N
JN
Schwartz
Robert J
RJ
Bruneau
Benoit G
BG
Lindsay
Elizabeth A
EA
Baldini
Antonio
A
D000483:Alleles; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004062:DiGeorge Syndrome / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D004396:Coloring Agents; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D008156:Luciferases; D001973:Bromodeoxyuridine