Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130041, China; Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Dev Biol. 2019 Aug 1;452(1):1-7. doi: 10.1016/j.ydbio.2019.04.013. Epub 2019 Apr 28.
Cardiomyocytes undergo dramatic changes during the fetal to neonatal transition stage to adapt to the new environment. The molecular and genetic mechanisms regulating these changes remain elusive. In this study, we showed Sema6D as a novel signaling molecule regulating perinatal cardiomyocyte proliferation and maturation. SEMA6D is a member of the Semaphorin family of signaling molecules. To reveal its function during cardiogenesis, we specifically inactivated Sema6D in embryonic cardiomyocytes using a conditional gene deletion approach. All mutant animals showed hypoplastic myocardial walls in neonatal hearts due to reduced cell proliferation. We further revealed that expression of MYCN and its downstream cell cycle regulators is impaired in late fetal hearts in which Sema6D is deleted, suggesting that SEMA6D acts through MYCN to regulate cardiomyocyte proliferation. In early postnatal mutant hearts, expression of adult forms of sarcomeric proteins is increased, while expression of embryonic forms is decreased. These data collectively suggest that SEMA6D is required to maintain late fetal/early neonatal cardiomyocytes at a proliferative and less mature status. Deletion of Sema6D in cardiomyocytes led to reduced proliferation and accelerated maturation. We further examined the consequence of these defects through echocardiographic analysis. Embryonic heart deletion of Sema6D significantly impaired the cardiac contraction of male adult hearts, while having a minor effect on female mutant hearts, suggesting that the effect of Sema6D-deletion in adult hearts is sex dependent.
心肌细胞在胎儿到新生儿过渡阶段会发生剧烈变化，以适应新环境。调节这些变化的分子和遗传机制仍不清楚。在这项研究中，我们发现 Sema6D 是一种调节围产期心肌细胞增殖和成熟的新型信号分子。SEMA6D 是信号分子 Semaphorin 家族的成员。为了揭示其在心脏发生过程中的功能，我们使用条件基因缺失方法特异性地在胚胎心肌细胞中失活 Sema6D。由于细胞增殖减少，所有突变动物的新生心脏都表现出心肌壁发育不全。我们进一步揭示，在 Sema6D 缺失的晚期胎心中，MYCN 的表达及其下游细胞周期调节剂的表达受损，表明 SEMA6D 通过 MYCN 调节心肌细胞增殖。在早期新生突变心脏中，成年形式的肌节蛋白的表达增加，而胚胎形式的表达减少。这些数据共同表明，SEMA6D 是维持晚期胎儿/早期新生儿心肌细胞增殖和较少成熟状态所必需的。心肌细胞中 Sema6D 的缺失导致增殖减少和成熟加速。我们通过超声心动图分析进一步研究了这些缺陷的后果。胚胎心脏中 Sema6D 的缺失显著损害了雄性成年心脏的心脏收缩功能，而对雌性突变心脏的影响较小，这表明 Sema6D 缺失在成年心脏中的作用是性别依赖性的。
