Koibuchi Nobutaka, Chin Michael T
Vascular Medicine Research, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Circ Res. 2007 Mar 30;100(6):850-5. doi: 10.1161/01.RES.0000261693.13269.bf. Epub 2007 Mar 1.
We previously reported that mice lacking the hairy-related basic helix-loop-helix (bHLH) transcription factor CHF1/Hey2 develop a thin-walled left ventricle. To explore the basis for this phenotype, we examined regional gene expression patterns in the developing myocardium. We found that atrial natriuretic factor (ANF), which is normally expressed in the atria and trabeculae and is restricted from the developing compact myocardium beginning at embryonic day 13.5, is persistently expressed in the left ventricular compact myocardium of the knockout animals. We also examined the expression pattern of the T-box transcription factor Tbx5, a known regulator of ANF, and an additional Tbx5-dependent gene, connexin 40 (Cx40), both of which share a similar expression pattern to ANF during development. Tbx5 and Cx40 were similarly expressed ectopically in the compact myocardium of the CHF1/Hey2 knockout mouse. The atrial contractile genes mlc1a and mlc2a were also expressed ectopically in the left ventricular compact myocardium, providing evidence for a general dysregulation of atrial gene expression. Crossing of a myocardial-specific CHF1/Hey2 transgenic mouse with the knockouts led to rescue of the thin-walled myocardial phenotype and restoration of the normal patterns of gene expression. Myocardial cell proliferation, which has been shown previously to be suppressed by Tbx5, was also decreased in the knockout mice and rescued by the transgene. Our findings suggest that CHF1/Hey2 suppresses atrial identity in the left ventricular compact myocardium, facilitates myocardial proliferation by suppressing Tbx5, and thereby promotes proper ventricular myocardial maturation.
我们之前报道过，缺乏与毛相关的碱性螺旋-环-螺旋（bHLH）转录因子CHF1/Hey2的小鼠会发育出薄壁左心室。为了探究这种表型的基础，我们检查了发育中心肌的区域基因表达模式。我们发现，心房利钠因子（ANF）通常在心房和小梁中表达，从胚胎第13.5天开始在发育中的致密心肌中受到限制，但在基因敲除动物的左心室致密心肌中持续表达。我们还检查了T-box转录因子Tbx5的表达模式，Tbx5是已知的ANF调节因子，以及另一个Tbx5依赖性基因连接蛋白40（Cx40），在发育过程中它们两者与ANF具有相似的表达模式。Tbx5和Cx40在CHF1/Hey2基因敲除小鼠的致密心肌中也同样异位表达。心房收缩基因mlc1a和mlc2a也在左心室致密心肌中异位表达，这为心房基因表达的普遍失调提供了证据。将心肌特异性CHF1/Hey2转基因小鼠与基因敲除小鼠杂交，导致薄壁心肌表型得到挽救，基因表达恢复正常模式。心肌细胞增殖先前已被证明受Tbx5抑制，在基因敲除小鼠中也减少，并被转基因挽救。我们的研究结果表明，CHF1/Hey2抑制左心室致密心肌中的心房特征，通过抑制Tbx5促进心肌增殖，从而促进心室心肌的正常成熟。
