title: Temporally Distinct Six2-Positive Second Heart Field Progenitors Regulate Mammalian Heart Development and Disease.
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.
authors.affiliation: 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.
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Departments of Urology and Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jingying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Urology and Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Chaoshe
authors.initials: C
authors.lastname: Guo
authors.affiliation: Divisions of Genetics and Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weiting
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China. Electronic address: tanganqier@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D004452:Echocardiography; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006321:Heart / Q000254:growth & development*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D016296:Mutagenesis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; C465570:Shh protein, mouse; C497420:Six2 protein, mouse; D014157:Transcription Factors; D013629:Tamoxifen
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