Cfdp1 is Essential for Cardiac Development and Function

Abstract

Cardiovascular diseases (CVDs) are the prevalent cause of mortality worldwide and account for the most common noncommunicable disease. CVDs describe a wide spectrum of disorders affecting the proper function, physiology and morphogenesis of the heart and blood vessels. The risk of developing cardiovascular diseases is modulated by a combination of environmental and genetic effectors. Thus, its highly important to identify candidate genes and elucidate their role in the manifestation of the disease. Large-scale human studies have revealed the implication of Craniofacial Development Protein 1 (CFDP1) in coronary artery disease (CAD). CFDP1 belongs to the evolutionary conserved Bucentaur (BCNT) family and up to date, its function and mechanism of action in Cardiovascular Development is still unclear. In this study, we utilize zebrafish to investigate the role of cfdp1 in the developing heart due to the high genomic homology, similarity in heart physiology and the ease of experimentally manipulation. We showed that cfdp1 is expressed during development and at 120 hours post fertilization its expression is restricted to the region of the heart and the head. We then generated a cfdp1-null zebrafish line using CRISPR-Cas9 system which led to a lethal phenotype since knockout embryos do not reach adulthood. cfdp1-/- embryos develop arrhythmic hearts and defective cardiac performance exhibiting statistically significant differences in heart features including End Diastolic Volume, Cardiac Output, Ejection Fraction and Stroke Volume. Myocardial trabeculation is also impaired in cfdp1-/- embryonic hearts, implying its regulatory role also in this developmental process. Findings from both knockdown and knockout experiments showed that abrogation of cfdp1 leads to downregulation of Wnt signaling in embryonic hearts during valve development but without affecting Notch activation in this process.