Ventricular expression of tbx5 inhibits normal heart chamber development.
The T-box gene tbx5 is expressed in the developing heart, forelimb, eye, and liver in vertebrate embryos during critical stages of morphogenesis and patterning. In humans, mutations in the TBX5 gene have been associated with Holt-Oram syndrome, which is characterized by developmental anomalies in the heart and forelimbs. In chicken and mouse embryos, tbx5 expression is initiated at the earliest stages of heart formation throughout the heart primordia and is colocalized with other cardiac transcription factors such as nkx-2.5 and GATA4. As the heart differentiates, tbx5 expression is restricted to the posterior sinoatrial segments of the heart, consistent with the timing of atrial chamber determination. The correlation between tbx5 expression and atrial lineage determination was examined in retinoic acid (RA)-treated chicken embryos. tbx5 expression is maintained throughout the hearts of RA-treated embryos under conditions that also expand atrial-specific gene expression. The downstream effects of persistent tbx5 expression in the ventricles were examined directly in transgenic mice. Embryos that express tbx5 driven by a beta-myosin heavy chain promoter throughout the primitive heart tube were generated. Loss of ventricular-specific gene expression and retardation of ventricular chamber morphogenesis were observed in these embryos. These studies provide direct evidence for an essential role for tbx5 in early heart morphogenesis and chamber-specific gene expression.
Liberatore
C M
CM
Division of Molecular Cardiovascular Biology, The Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
Searcy-Schrick
R D
RD
Yutzey
K E
KE
D000818:Animals; D024743:Atrial Myosins; D030161:Avian Proteins; D002642:Chick Embryo; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004622:Embryo, Mammalian / Q000378:metabolism; D050991:GATA4 Transcription Factor; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000096:biosynthesis; D017403:In Situ Hybridization; D000432:Methanol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D009218:Myosins / Q000096:biosynthesis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology; D029867:Xenopus Proteins
D030161:Avian Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D016372:RNA, Antisense; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D029867:Xenopus Proteins; D014212:Tretinoin; D024743:Atrial Myosins; C094463:AMHC1 protein, chicken; D018995:Myosin Heavy Chains; D009218:Myosins; D000432:Methanol