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.

CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries

“…38 Mice null for Hey1, a Notch downstream transcription factor, also exhibited defects in the formation of the 4th PAA, resulting in a right-sided aortic arch (RAA), IAA, and aberrant origin of the right subclavian artery (A-RSA). 40 Endothelin-converting enzyme-1 (Ece1)and the endothelin receptor type A (Ednra)-null mice exhibit a rightsided aortic arch and double aortic arches associated with enlargement of the 3rd PAA and the impaired regression of the 4th and 6th PAAs. 41 Although the AA anomaly and pulmonary artery phenotypes in Cxcl12-null mice were in complete penetrance, there may be a variance caused by a mixed strain background.…”

Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4)

“…Defects in the development and/or remodeling of pharyngeal arch arteries result in various malformations such as an interrupted aortic arch, a right-sided aortic arch and an aberrant origin of the right subclavian artery in humans [ 36 ]. In mouse models, formation and remodeling of pharyngeal arch arteries has been shown to involve multiple signaling molecules including integrins, endothelins , the transforming growth factor β superfamily, Notch receptors and the Hrt1/Hey1 transcription factor [ 29 , 37 – 41 ].…”

Significance of Transcription Factors in the Mechanisms of Great Artery Malformations

“…The malformation of great arteries in Hey1 knockout mice is also associated with the fourth PAA defect although the expression of Tbx1 and target genes as well as the behavior of neural crest cells are normal [2]. Interestingly, the tubular endothelial structure is disturbed, and the expression of a Notch ligand, Jagged1, in endothelial cells is markedly reduced in the defective fourth PAAs of Hey1 knockout embryos (Fig.…”

“…Interestingly, the tubular endothelial structure is disturbed, and the expression of a Notch ligand, Jagged1, in endothelial cells is markedly reduced in the defective fourth PAAs of Hey1 knockout embryos (Fig. 60.1) [2], suggesting that Hey1 is necessary for the endothelial organization of the fourth PAA. Elucidating the mechanism of Hey actions, especially…”

“…Among them, we recently reported that Hey1 had an indispensable role for the great artery formation (Fig. 60.1) [2].…”