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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Echocardiography
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Heart / growth & development*
  • Heart Diseases / metabolism
  • Heart Diseases / pathology
  • Heart Ventricles / diagnostic imaging
  • Heart Ventricles / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • In Situ Hybridization, Fluorescence
  • Mice
  • Mutagenesis
  • Myocardium / cytology
  • Myocardium / metabolism
  • RNA, Messenger / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • Tamoxifen / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ventricular Function / physiology

Substances

  • Hedgehog Proteins
  • Homeodomain Proteins
  • RNA, Messenger
  • Selective Estrogen Receptor Modulators
  • Shh protein, mouse
  • Six2 protein, mouse
  • Transcription Factors
  • Tamoxifen