Wnt and Notch Regulation of Cardiac and Vascular Smooth Muscle Gene Expression During Differentiation.

在心血管发育过程中，心脏和向身体和肺部输送血液的大血管至少来自胚胎内的三个来源。这些包括第一和第二心脏区域以及一组从颅底迁移形成离开心脏的大血管的神经嵴细胞。有趣的是，第二心脏区域细胞最终将成为右心室的心肌细胞和大血管的血管平滑肌细胞。然而，决定心脏和平滑肌专长之间选择的机制仍然未知。更一般地说，细胞特化的调节是通过分泌因子和细胞间接触来调节的。 Wnt 和 Notch 信号分子家族以这种方式调节细胞特化，并代表了决定多个生物系统中器官形成的关键发育线索。然而，这些信号通路在心血管发育以及心脏或血管平滑肌组织特化中的作用尚不清楚。有趣的是，对小鼠心肌细胞增强因子 2C (MEF2C) 基因的遗传抑制揭示了该转录因子在心脏第二心区和神经嵴特化中的关键作用。因此，本研究利用细胞和分子生物学技术，提出检验Wnt和Notch信号通路通过调节MEF2C活性来调节心脏和血管平滑肌特化的假设。这一实验目标的完成将为我们对心血管发育这一方面的理解提供新的分子见解，这可能对未来旨在破译影响心脏的后天和遗传缺陷的应用研究至关重要。

During cardiovascular development, the heart and the great vessels that deliver blood to the body and lungs arise from at least three sources within the embryo. These include the first and second heart fields and a group of neural crest cells that migrate from the base of the skull to form the large vessels leaving the heart. Interestingly, the second heart field cells will ultimately become both heart muscle of the right ventricle and vascular smooth muscle cells of the great vessels. However, the mechanisms that determine this choice between heart and smooth muscle speciality remains unknown. Regulation of cell specialization, more generally, is regulated by secreted factors and cell-to-cell contact. The Wnt and Notch families of signaling molecules regulate cell specialization in this manner, and represent critical developmental cues that dictate organ formation in multiple biological systems. However, the role of these signaling pathways in cardiovascular development, as well as in the specialization of heart or vascular smooth muscle tissue is less understood. Interestingly, genetic inhibition of the myocyte enhancer factor 2C (MEF2C) gene in mice has uncovered a critical role for this transcription factor in cardiac second heart field and neural crest specialization. Therefore, utilizing techniques of cell and molecular biology, this research proposes to test the hypothesis that Wnt and Notch signaling pathways regulate cardiac and vascular smooth muscle specialization through modulation of MEF2C activity. Completion of this experimental objective will provide a new molecular insight into our understanding of this aspect of cardiovascular development, which could prove to be critical for future applied studies aimed at deciphering acquired and genetic defects affecting the heart.