Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function

• Published in: PloS one 2019-03, Vol.14 (3), p.e0212992
• Main Authors: Dupays, Laurent, Towers, Norma, Wood, Sophie, David, Anna, Stuckey, Daniel J, Mohun, Timothy
• Format: Article
• Language: English
• Subjects: Ablation; Ablation (Surgery); Abnormalities; Animal genetic engineering; Animals; Biology and Life Sciences; Bone Morphogenetic Proteins - metabolism; Cardiomyocytes; Cardiovascular disease; Cell Differentiation - genetics; Cell Proliferation - genetics; Cells (biology); Clonal deletion; Cloning; Congenital diseases; Crick, Francis; CRISPR; CRISPR-Cas Systems; Developmental biology; Differentiation; EDTA; Elongation; Embryo, Mammalian; Embryos; Experiments; Furin; Furin - genetics; Furin - metabolism; Gene deletion; Gene Expression Regulation, Developmental; Genetic aspects; Genetic engineering; Heart; Heart - embryology; Heart cells; Heart function; Homeobox; Homeobox Protein Nkx-2.5 - metabolism; Medicine and Health Sciences; Mice; Mice, Transgenic; Models, Animal; Morphogenesis; Mutagenesis; Mutation; Myocardium - metabolism; Myocytes, Cardiac - physiology; Nkx2.5 protein; Organogenesis - genetics; Phenotypes; Progenitor cells; Proprotein convertases; Research and Analysis Methods; Rodents; Stem cells; Stem Cells - physiology; Transcription (Genetics); Ultrasonic imaging
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212992

The homeodomain transcription factor NKX2-5 is known to be essential for both normal heart development and for heart function. But little is yet known about the identities of its downstream effectors or their function during differentiation of cardiac progenitor cells (CPCs). We have used transgenic analysis and CRISPR-mediated ablation to identify a cardiac enhancer of the Furin gene. The Furin gene, encoding a proprotein convertase, is directly repressed by NKX2-5. Deletion of Furin in CPCs is embryonic lethal, with mutant hearts showing a range of abnormalities in the outflow tract. Those defects are associated with a reduction in proliferation and premature differentiation of the CPCs. Deletion of Furin in differentiated cardiomyocytes results in viable adult mutant mice showing an elongation of the PR interval, a phenotype that is consistent with the phenotype of mice and human mutant for Nkx2-5. Our results show that Furin mediate some aspects of Nkx2-5 function in the heart.