Abstract
Although retinoic acid (RA) teratogenicity has been investigated for decades, the mechanisms underlying RA-induced outflow tract (OFT) malformations are not understood. Here, we show zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects resulting from two mechanisms: first, a failure of second heart field (SHF) progenitors to join the OFT, instead contributing to the pharyngeal arch arteries (PAAs), and second, a loss of first heart field (FHF) ventricular cardiomyocytes due to disrupted cell polarity and extrusion from the heart tube. Molecularly, excess RA signaling negatively regulates fibroblast growth factor 8a (fgf8a) expression and positively regulates matrix metalloproteinase 9 (mmp9) expression. Although restoring Fibroblast growth factor (FGF) signaling can partially rescue SHF addition in Cyp26 deficient embryos, attenuating matrix metalloproteinase (MMP) function can rescue both ventricular SHF addition and FHF integrity. These novel findings indicate a primary effect of RA-induced OFT defects is disruption of the extracellular environment, which compromises both SHF recruitment and FHF ventricular integrity.
Highlights
The heart is the first organ to develop and function in all vertebrates
We find that Cyp26-deficient zebrafish embryos fail to add later-differentiating ventricular cardiac progenitors to the outflow tract (OFT), with some of these progenitors instead contributing to the nearby arch arteries
We find that ventricular OFT defects in Cyp26-deficient embryos are predominantly caused by a parallel increase in matrix metalloproteinase 9 expression
Summary
The heart is the first organ to develop and function in all vertebrates. Improper heart development can lead to congenital heart defects (CHDs), which impinge on normal embryogenesis and can result in embryonic or neonatal lethality [1,2]. Construction of a functional vertebrate heart requires the precisely coordinated development of two sources of cardiomyocyte progenitors [3]. Progenitors within the anterior lateral plate mesoderm give rise to early-differentiating cardiomyocytes of the first heart field (FHF), which generate the initial heart tube [3,4]. Progenitors within the adjacent, medial pharyngeal mesoderm give rise to later-differentiating cardiomyocytes of the second heart field (SHF), which augments the heart through accretion to both the arterial and venous poles [3,4]. Despite advances in understanding many of the intricate signaling mechanisms that direct appropriate SHF development in vertebrates, the molecular etiologies underlying OFT defects still remain poorly understood
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