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The 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.
Pubmed ID: 30578278
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Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.
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View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
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