Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis.
Extensive misexpression studies were carried out to explore the roles played by Tbx5, the expression of which is excluded from the right ventricle (RV) during cardiogenesis. When Tbx5 was misexpressed ubiquitously, ventricular septum was not formed, resulting in a single ventricle. In such heart, left ventricle (LV)-specific ANF gene was induced. In search of the putative RV factor(s), we have found that chick Tbx20 is expressed in the RV, showing a complementary fashion to Tbx5. In the Tbx5-misexpressed heart, this gene was repressed. When misexpression was spatially partial, leaving small Tbx5-negative area in the right ventricle, ventricular septum was shifted rightwards, resulting in a small RV with an enlarged LV. Focal expression induced an ectopic boundary of Tbx5-positive and -negative regions in the right ventricle, at which an additional septum was formed. Similar results were obtained from the transient transgenic mice. In such hearts, expression patterns of dHAND and eHAND were changed with definitive cardiac abnormalities. Furthermore, we report that human ANF promoter is synergistically activated by Tbx5, Nkx2.5 and GATA4. This activation was abrogated by Tbx20, implicating the pivotal roles of interactions among these heart-specific factors. Taken together, our data indicate that Tbx5 specifies the identity of LV through tight interactions among several heart-specific factors, and highlight the essential roles of Tbx5 in cardiac development.
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0101, Japan.
Jun K
JK
Takeuchi
Makoto
M
Ohgi
Kazuko
K
Koshiba-Takeuchi
Hidetaka
H
Shiratori
Ichiro
I
Sakaki
Keiko
K
Ogura
Yukio
Y
Saijoh
Toshihiko
T
Ogura
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D006346:Heart Septum / Q000033:anatomy & histology* / Q000196:embryology* / Q000502:physiology; D006352:Heart Ventricles / Q000033:anatomy & histology* / Q000196:embryology*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D016276:Ventricular Function; D029961:Zebrafish Proteins
D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C498765:HAND2 protein, human; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse; C103172:T-box transcription factor 5; C410915:hand2 protein, zebrafish; C097341:helix-loop-helix protein, eHAND