title: Pharyngeal arch artery defects and lethal malformations of the aortic arch and its branches in mice deficient for the Hrt1/Hey1 transcription factor.
abstract: The aortic arch and major branch arteries are formed from the three pairs of pharyngeal arch arteries (PAAs) during embryonic development. Their morphological defects are clinically observed as isolated diseases, as a part of complicated cardiovascular anomalies or as a manifestation of multi-organ syndromes such as 22q11.2 deletion syndrome. Although numerous genes have been implicated in PAA formation and remodeling, detailed mechanisms remain poorly understood. Here we report that the mice null for Hrt1/Hey1, a gene encoding a downstream transcription factor of Notch and ALK1 signaling pathways, show perinatal lethality on the C57BL/6N, C57BL/6N × C57BL/6J or C57BL/6N × 129X1/SvJ background. Hrt1/Hey1 null embryos display abnormal development of the fourth PAA (PAA4), which results in congenital vascular defects including right-sided aortic arch, interruption of the aortic arch and aberrant origin of the right subclavian artery. Impaired vessel formation occurs randomly in PAA4 of Hrt1/Hey1 null embryos, which likely causes the variability of congenital malformations. Endothelial cells in PAA4 of null embryos differentiate normally but are structurally disorganized at embryonic day 10.5 and 11.5. Vascular smooth muscle cells are nearly absent in the structurally-defective PAA4, despite the appropriate migration of cardiac neural crest cells into the fourth pharyngeal arches. Endothelial expression of Jag1 is down-regulated in the structurally-defective PAA4 of null embryos, which may be one of the mechanisms underlying the suppression of vascular smooth muscle cell differentiation. While the direct downstream phenomena of the Hrt1/Hey1 deficiency remain to be clarified, we suggest that Hrt1/Hey1-dependent transcriptional regulation has an important role in PAA formation during embryonic development.
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Sakabe
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ioka
authors.affiliation: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kinugasa-Katayama
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Tsuchihashi
authors.affiliation: Department of Pathology, The University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Utset
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamagishi
authors.affiliation: Laboratory for Cardiovascular System Research, Nara Medical University Advanced Medical Research Center, Kashihara, Nara, Japan; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. Electronic address: osamu.nakagawa@ncvc.go.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities* / Q000196:embryology; D017209:Apoptosis; D001934:Branchial Region / Q000098:blood supply / Q000196:embryology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000196:embryology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D017384:Sequence Deletion
chemical_list: D018797:Cell Cycle Proteins; C120420:Hey1 protein, mouse; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein
keywords: Cardiovascular development; Congenital vascular malformations; Hairy-related transcription factors; Knockout mouse; Notch signaling; Pharyngeal arch artery defects