The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch
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),...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-01-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/12/1/dmm036491 |
| _version_ | 1818309263052767232 |
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| author | Kelsey F. Sugrue Anjali A. Sarkar Linda Leatherbury Irene E. Zohn |
| author_facet | Kelsey F. Sugrue Anjali A. Sarkar Linda Leatherbury Irene E. Zohn |
| author_sort | Kelsey F. Sugrue |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T07:27:23Z |
| format | Article |
| id | doaj.art-f16d777b16254fa69d0b0a1b290402cf |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-13T07:27:23Z |
| publishDate | 2019-01-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-f16d777b16254fa69d0b0a1b290402cf2022-12-21T23:55:17ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-01-0112110.1242/dmm.036491036491The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic archKelsey F. Sugrue0Anjali A. Sarkar1Linda Leatherbury2Irene E. Zohn3 Institute for Biomedical Sciences, The George Washington University, Washington, DC 20037, USA Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA Children's National Heart Institute, Children's National Health System, George Washington University School of Medicine, Washington, DC 20010, USA Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA 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.http://dmm.biologists.org/content/12/1/dmm036491Congenital heart defectsHectd1Retinoic acidVitamin A deficiencyAortic arch development |
| spellingShingle | Kelsey F. Sugrue Anjali A. Sarkar Linda Leatherbury Irene E. Zohn The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch Disease Models & Mechanisms Congenital heart defects Hectd1 Retinoic acid Vitamin A deficiency Aortic arch development |
| title | The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch |
| title_full | The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch |
| title_fullStr | The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch |
| title_full_unstemmed | The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch |
| title_short | The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch |
| title_sort | ubiquitin ligase hectd1 promotes retinoic acid signaling required for development of the aortic arch |
| topic | Congenital heart defects Hectd1 Retinoic acid Vitamin A deficiency Aortic arch development |
| url | http://dmm.biologists.org/content/12/1/dmm036491 |
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