Abstract
ABSTRACTThe development of the aortic arch is a complex process that involves remodeling of the bilaterally symmetrical pharyngeal arch arteries (PAAs) into the mature asymmetric aortic arch. Retinoic acid signaling is a key regulator of this process by directing patterning of the second heart field (SHF), formation of the caudal PAAs and subsequent remodeling of the PAAs to form the aortic arch. Here, we identify the HECTD1 ubiquitin ligase as a novel modulator of retinoic acid signaling during this process. Hectd1opm/opm homozygous mutant embryos show a spectrum of aortic arch abnormalities that occur following loss of 4th PAAs and increased SHF marker expression. This sequence of defects is similar to phenotypes observed in mutant mouse models with reduced retinoic acid signaling. Importantly, HECTD1 binds to and influences ubiquitination of the retinoic acid receptor, alpha (RARA). Furthermore, reduced activation of a retinoic acid response element (RARE) reporter is detected in Hectd1 mutant cells and embryos. Interestingly, Hectd1opm/+ heterozygous embryos exhibit reduced retinoic acid signaling, along with intermediate increased expression of SHF markers; however, heterozygotes show normal development of the aortic arch. Decreasing retinoic acid synthesis by reducing Raldh2 (also known as Aldh1a2) gene dosage in Hectd1opm/+ heterozygous embryos reveals a genetic interaction. Double heterozygous embryos show hypoplasia of the 4th PAA and increased incidence of a benign aortic arch variant, in which the transverse arch between the brachiocephalic and left common carotid arteries is shortened. Together, our data establish that HECTD1 is a novel regulator of retinoic acid signaling required for proper aortic arch development.
Highlights
Congenital heart defects (CHDs) are the most common structural birth defects in humans, occurring in approximately 1% of live births with abnormalities of the outflow tract and the aortic arch accounting for 20-30% of all CHDs (Bruneau, 2008; Creazzo et al, 1998; Fahed et al, 2013; Lloyd-Jones et al, 2009)
Retinoic acid signaling is a key regulator of this process by directing patterning of the second heart field (SHF), formation of the caudal pharyngeal arch arteries (PAAs) and subsequent remodeling of the PAAs to form the aortic arch
We identify the HECTD1 ubiquitin ligase as a novel modulator of retinoic acid signaling during this process
Summary
Congenital heart defects (CHDs) are the most common structural birth defects in humans, occurring in approximately 1% of live births with abnormalities of the outflow tract and the aortic arch accounting for 20-30% of all CHDs (Bruneau, 2008; Creazzo et al, 1998; Fahed et al, 2013; Lloyd-Jones et al, 2009). There are a number of normal anatomical aortic arch variants found in the human population with the most common being a common origin for the brachiocephalic artery and left common carotid arteries. This variant occurs in 10-20% of the population and is sometimes called a “bovine arch” because of structural similarities to aortic arch of cattle; the variant in humans is not a true bovine arch since in cattle, there is a single brachiocephalic trunk origin for the carotid and subclavian arteries (Moorehead et al, 2016; Shaw et al, 2003; Spacek and Veselka, 2012; Stewart, 1964). The underlying cause of these normal anatomical variants remains unknown
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