Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression

• Published in: Development (Cambridge) Vol. 145; no. 3; p. dev161497
• Main Authors: Colombo, Sophie, de Sena-Tomás, Carmen, George, Vanessa, Werdich, Andreas A, Kapur, Sunil, MacRae, Calum A, Targoff, Kimara L
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.02.2018
• Subjects: Animals; Animals, Genetically Modified; Body Patterning - genetics; Cardiomyocytes; Cell Differentiation; Cell Proliferation; Conduction; Danio rerio; Gene Expression Regulation, Developmental; Gene mapping; Genes; Heart; Heart - embryology; Heart Defects, Congenital - embryology; Heart Defects, Congenital - genetics; Heart diseases; Homeobox; Homeobox Protein Nkx-2.5 - genetics; Homeodomain Proteins - genetics; Humans; Islet-1 protein; LIM-Homeodomain Proteins - genetics; Mutation; Myoblasts, Cardiac - cytology; Myoblasts, Cardiac - metabolism; Nkx2.5 protein; Subpopulations; Transcription Factors - genetics; Ventricle; Zebrafish Proteins - genetics; nkx2.7; Zebrafish; Arterial pole; Second heart field; nkx2.5; Venous pole
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.161497

is the most commonly mutated gene associated with human congenital heart defects (CHDs), with a predilection for cardiac pole abnormalities. This homeodomain transcription factor is a central regulator of cardiac development and is expressed in both the first and second heart fields (FHF and SHF). We have previously revealed essential functions of and , two homologs expressed in zebrafish cardiomyocytes, in maintaining ventricular identity. However, the differential roles of these genes in the specific subpopulations of the anterior (aSHF) and posterior (pSHF) SHFs have yet to be fully defined. Here, we show that Nkx genes regulate aSHF and pSHF progenitors through independent mechanisms. We demonstrate that Nkx genes restrict proliferation of aSHF progenitors in the outflow tract, delimit the number of pSHF progenitors at the venous pole and pattern the sinoatrial node acting through Isl1 repression. Moreover, optical mapping highlights the requirement for Nkx gene dose in establishing electrophysiological chamber identity and in integrating the physiological connectivity of FHF and SHF cardiomyocytes. Ultimately, our results may shed light on the discrete errors responsible for -dependent human CHDs of the cardiac outflow and inflow tracts.