The embryonic process of forming a complex structure such as the heart remains poorly understood. Here, we show that Six2 marks a dynamic subset of second heart field progenitors. Six2-positive (Six2+) progenitors are rapidly recruited and assigned, and their descendants are allocated successively to regions of the heart from the right ventricle (RV) to the pulmonary trunk. Global ablation of Six2+ progenitors resulted in RV hypoplasia and pulmonary atresia. An early stage-specific ablation of a small subset of Six2+ progenitors did not cause any apparent structural defect at birth but rather resulted in adult-onset cardiac hypertrophy and dysfunction. Furthermore, Six2 expression depends in part on Shh signaling, and Shh deletion resulted in severe deficiency of Six2+ progenitors. Collectively, these findings unveil the chronological features of cardiogenesis, in which the mammalian heart is built sequentially by temporally distinct populations of cardiac progenitors, and provide insights into late-onset congenital heart disease.
Keywords: DTA; HREM; PTA; Shh; Six1; Six2; TOF; cardiac neural crest; cardiac outflow tract; common arterial trunk; diphtheria toxin fragment A; high-resolution episcopic microscopy; intrapericardial arterial trunk; persistent truncus arteriosus; progenitor; second heart field; tetralogy of Fallot.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.