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.

Development of the human heart

“…As a consequence, the OFT has a nonmyocardial portion in between its distal of myocardial border and the border of the pericardial cavity. This nonmyocardial portion of the OFT will become the intrapericardial part of the aorta and pulmonary trunk (Rana et al, ; Sizarov et al, ).The cells of the nonmyocardial portion originate from both the second‐heart field and the cardiac neural crest (Cai et al, ; Jiang, Rowitch, Soriano, McMahon, & Sucov, ; Zhou et al, ).…”

“…This nonmyocardial portion of the OFT will become the intrapericardial part of the aorta and pulmonary trunk (Rana et al, 2007;Sizarov et al, 2012).The cells of the nonmyocardial portion originate from both the second-heart field and the cardiac neural crest (Cai et al, 2003;Jiang, Rowitch, Soriano, McMahon, & Sucov, 2000;Zhou et al, 2017).…”

A single cell transcriptional roadmap for cardiopharyngeal fate diversification

“…However, Dach homologs are part of a conserved regulatory network, termed "the retinal network" (Kumar, 2009) , which comprises homologs of Six, EyA and Pax family transcription factors, and studies have uncovered a role for Six and EyA genes in the mouse SHF (Guo et al, 2011;Zhou et al, 2017) . To investigate the function of Ciona Dach in SHP fate specification, we employed lineage-specific CRISPR/Cas9-mediated loss-of-function assays (Gandhi et al, 2017;Stolfi et al, 2014b) .…”

“…Notably, together with Pax , Six and Eya family genes, Dach homologs form a conserved "retinal network" (Davis and Rebay, 2017;Kumar, 2009) . In the mouse, Six and Eya homologs have been implicated in early SHF development (Guo et al, 2011;Zhou et al, 2017) , opening the possibility that conserved elements of the retinal network contribute to SHF-specific gene expression.…”

Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development

“…This suggests that the aortic and pulmonary trunks are derived from cNCCs and SHF progenitors, respectively 8 . Because cNCCs and the SHF are essential for proper development of the OFT 9 , understanding the mechanisms that regulate the development of cNCCs and their interactions with the SHF will allow these findings to be applied in clinical practice.…”