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Cell Rep. 2017 Jan 24;18(4):1019-1032. doi: 10.1016/j.celrep.2017.01.002.

Temporally Distinct Six2-Positive Second Heart Field Progenitors Regulate Mammalian Heart Development and Disease.

Author information

1
Departments of Urology and Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
2
Departments of Urology and Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
3
Divisions of Genetics and Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
4
Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
5
Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China. Electronic address: tanganqier@163.com.
6
Departments of Urology and Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: sean.li@childrens.harvard.edu.

Abstract

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

PMID:
28122228
DOI:
10.1016/j.celrep.2017.01.002
[Indexed for MEDLINE]
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