Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.
PLoS One. 2007 Apr 25;2(4):e398. doi: 10.1371/journal.pone.0000398.
The heart forms from a linear tube that is subject to complex remodeling during embryonic development. Hallmarks of this remodeling are the looping of the heart tube and the regionalization into chamber and non-chamber myocardium. Cardiomyocytes in the future chamber myocardium acquire different cellular and physiological characteristics through activation of a chamber-specific genetic program, which is in part mediated by T-box genes.
METHODOLOGY/PRINCIPAL FINDING: We characterize two new zebrafish T-box transcription factors, tbx3b and tbx2a, and analyze their role during the development of the atrioventricular canal. Loss- and gain-of-function analyses demonstrate that tbx3b and tbx2a are necessary to repress the chamber-genetic program in the non-chamber myocardium. We also show that tbx3b and tbx2a are required to control cell proliferation in the atrioventricular canal and that misregulation of cell proliferation in the heart tube influences looping. Furthermore, we characterize the heart phenotype of a novel Tbx3 mutation in mice and show that both the control of cell proliferation and the repression of chamber-specific genetic program in the non-chamber myocardium are conserved roles of Tbx3 in this species.
CONCLUSIONS/SIGNIFICANCE: Taken together, our results uncover an evolutionarily conserved role of Tbx2/3 transcription factors during remodeling of the heart myocardium and highlight the importance of controlling cell proliferation as a driving force of morphogenesis.
心脏从线性管形成，在胚胎发育过程中经历复杂的重塑。这种重塑的标志是心脏管的环化和腔室和非腔室心肌的区域化。未来腔室心肌中的心肌细胞通过激活腔室特异性基因程序获得不同的细胞和生理特征，该程序部分由 T 盒基因介导。
方法/主要发现：我们描述了两种新的斑马鱼 T 盒转录因子 tbx3b 和 tbx2a，并分析了它们在房室管发育过程中的作用。缺失和功能获得分析表明，tbx3b 和 tbx2a 是抑制非腔室心肌中腔室遗传程序所必需的。我们还表明，tbx3b 和 tbx2a 是控制房室管细胞增殖所必需的，并且心脏管中细胞增殖的失调会影响环化。此外，我们描述了小鼠中一种新型 Tbx3 突变的心脏表型，并表明 Tbx3 在该物种中的细胞增殖控制和非腔室心肌中腔室特异性基因程序的抑制都是保守作用。
结论/意义：总之，我们的结果揭示了 Tbx2/3 转录因子在心脏心肌重塑过程中的进化保守作用，并强调了控制细胞增殖作为形态发生驱动力的重要性。
