Semaphorin in the heart

Semaphorin was cloned as a potent neural chemorepellent and is known as a directional guidance molecule for nerve fibers. However, recent studies demonstrated that semaphorin family members have important roles in cardiovascular development and diseases. The cardiovascular system consists of many types of cells, including neural cells, and is extensively innervated and tightly regulated by the autonomic nervous system. To maintain cardiac function properly, innervation density is strictly determined by the balance between neural chemoattractant and chemorepellent. Nerve growth factor, a potent chemoattractant, is abundantly synthesized from cardiomyocytes, but the chemorepellent for cardiac nerves was not determined until recently. We found that Sema3a is strongly expressed in the trabecular layer in early-stage embryos, but is reduced after birth, forming an epicardial-to-endocardial transmural sympathetic innervation patterning. Both Sema3a-deficient and -overexpressed mice showed sudden cardiac death and lethal arrhythmias from disruption of proper innervation patterning. More recently, Nakano et al. reported that a nonsynonymous polymorphism in Sema3a DNA is a risk factor for human cardiac arrest with ventricular fibrillation. Sympathetic innervation patterning was disrupted in these patients, suggesting proper expression of Sema3a and innervation patterning are critical to maintain arrhythmia-free hearts. Sema3c is expressed in the cardiac outflow tract during development and is important in cardiovascular patterning. Gata6 regulates Sema3c expression, and disruption of the Gata6/Sema3c pathway leads to congenital heart disease in mouse and human. This review focuses on the recent progress of our understanding of heart development and disease, regulated by semaphorin family members, in mouse and human.