Abstract
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.
Highlights
Morphogenesis of the four-chambered heart involves the transition between different differentiation states of cardiac progenitors and is regulated at the transcriptional level
To confirm NKX2-5 binding on M10 we performed ChIP experiments using chromatin from samples prepared from the anterior heart field (AHF) and heart of embryonic day 9 (E9.5) embryos (Fig 1B)
Using chromatin prepared from these tissues [22] (Fig 1B), we found that NKX2-5 bound to the M10 region and the extent of binding was similar for both AHF and heart
Summary
Morphogenesis of the four-chambered heart involves the transition between different differentiation states of cardiac progenitors and is regulated at the transcriptional level. It has been shown to regulate the specification of cardiac progenitor cells (CPCs), the differentiation of cardiac chambers and to be necessary for the formation and maintenance of different elements of the cardiac conduction system [1, 3,4,5,6,7]. At the earliest stages of cardiac morphogenesis, Nkx, acts along with Bmp and phospho-Smad in a negative feedback loop to regulate the temporal balance between specification and differentiation of the cardiac progenitor pool [1]. Whilst the repressor effect of Nkx on the Bmp2-phospho-Smad pathway appears to be critical in regulating the size of the CPC pool, the molecular mechanisms behind that interaction are poorly understood.
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