Singh Manvendra K, Christoffels Vincent M, Dias José M, Trowe Mark-Oliver, Petry Marianne, Schuster-Gossler Karin, Bürger Antje, Ericson Johan, Kispert Andreas
Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Development. 2005 Jun;132(12):2697-707. doi: 10.1242/dev.01854. Epub 2005 May 18.
Tbx20, a member of the T-box family of transcriptional regulators, shows evolutionary conserved expression in the developing heart. In the mouse, Tbx20 is expressed in the cardiac crescent, then in the endocardium and myocardium of the linear and looped heart tube before it is restricted to the atrioventricular canal and outflow tract in the multi-chambered heart. Here, we show that Tbx20 is required for progression from the linear heart tube to a multi-chambered heart. Mice carrying a targeted mutation of Tbx20 show early embryonic lethality due to hemodynamic failure. A linear heart tube with normal anteroposterior patterning is established in the mutant. The tube does not elongate, indicating a defect in recruitment of mesenchyme from the secondary heart field, even though markers of the secondary heart field are not affected. Furthermore, dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail. Instead, Tbx2, Bmp2 and vinexin alpha (Sh3d4), genes normally restricted to regions of primary myocardium and lining endocardium, are ectopically expressed in the linear heart tube of Tbx20 mutant embryos. Because Tbx2 is both necessary and sufficient to repress chamber differentiation (Christoffels et al., 2004a; Harrelson et al., 2004), Tbx20 may ensure progression to a multi-chambered heart by repressing Tbx2 in the myocardial precursor cells of the linear heart tube destined to form the chambers.
Tbx20是T-box转录调节因子家族的成员之一，在心脏发育过程中呈现出进化上保守的表达模式。在小鼠中，Tbx20在心脏新月区表达，然后在线性和环状心管的内膜和心肌中表达，之后在多腔心脏中局限于房室管和流出道。在此，我们表明Tbx20是线性心管发育为多腔心脏所必需的。携带Tbx20靶向突变的小鼠由于血流动力学衰竭在胚胎早期死亡。突变体中形成了具有正常前后模式的线性心管。尽管第二心脏场的标志物未受影响，但该心管不伸长，这表明从第二心脏场募集间充质存在缺陷。此外，心管的背腹模式形成、工作心肌的形成、环状化以及进一步的分化和形态发生均失败。相反，Tbx2、Bmp2和vinexin alpha（Sh3d4）这些通常局限于原心肌和内膜区域的基因，在Tbx20突变胚胎的线性心管中异位表达。由于Tbx2对于抑制腔室分化既是必需的也是充分的（Christoffels等人，2004a；Harrelson等人，2004），Tbx20可能通过在线性心管中注定要形成腔室的心肌前体细胞中抑制Tbx2，来确保发育为多腔心脏。
