<i>Pax9</i> is required for cardiovascular development and interacts with <i>Tbx1</i> in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis

Phillips, Helen M.; Stothard, Catherine A.; Qureshi, Wasay Mohiuddin Shaikh; Kousa, Anastasia I.; Briones-Leon, J. Alberto; Khasawneh, Ramada R.; O'Loughlin, Chloe; Sanders, Rachel; Mazzotta, Silvia; Dodds, Rebecca; Seidel, Kerstin; Bates, Timothy; Nakatomi, Mitsushiro; Cockell, Simon; Schneider, Jürgen; Mohun, Timothy J.; Maehr, René; Kist, Ralf; Peters, Heiko; Bamforth, Simon D.

doi:10.1242/dev.177618

Cited by 28 publications

(86 citation statements)

References 78 publications

(117 reference statements)

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“…2h, yellow arrow), right-sided AA and retroesophageal left subclavian artery (R-LCC, associated with right-sided AA). A similar decrease in the penetrance of AA anomalies between E10.5 and foetal stages has been observed in mouse knockout models 23,24 . This might result from increased lethality of embryos with Representative 3D Amira reconstructions of OFT cushions from manually segmented HREM data showing dorsal (h-l) and ventral (h'-l') views of (h) E12.5 control embryo, (i) normally rotated OFT from E12.5 ID embryo, (j) partially rotated OFT from E12.5 ID embryo, (k) non-rotated OFT from E12.5 ID embryo, (l) E11.5 control embryo.…”

Section: Resultssupporting

confidence: 77%

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

et al. 2021

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Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.

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Section: Resultssupporting

confidence: 77%

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

et al. 2021

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“…These included interrupted AA (IAA), aberrant right subclavian artery (A-RSA, Figure 2h, yellow arrow), right-sided AA and retroesophageal left subclavian artery (R-LCC, associated with right-sided AA). A similar decrease in the penetrance of AA anomalies between E10.5 and foetal stages has been observed in mouse knockout models 20,21 . Litter size did not differ significantly between E10.5 and E15.5 (Extended Figure 1i, P=0.7283), thus this did not result from increased lethality of embryos with abnormal AA formation prior to E15.5.…”

Section: Id Embryos Have Cardiovascular Defectssupporting

confidence: 77%

Maternal iron deficiency perturbs embryonic cardiovascular development

Kalisch-Smith

Ved

Szumska

et al. 2020

Preprint

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Congenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.

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“…The 22q11DS gene Tbx1 is known to interact with many genes in cardiovascular development, including Pax9 [24,25] and Gbx2 [24]. Pax9 is specifically expressed in the pharyngeal endoderm at embryonic day (E) 9.5 [26], although it is later expressed in the craniofacial region and skeleton.…”

Section: Introductionmentioning

confidence: 99%

“…Pax9 is specifically expressed in the pharyngeal endoderm at embryonic day (E) 9.5 [26], although it is later expressed in the craniofacial region and skeleton. Mice deficient for Pax9 die perinatally with a cleft palate, absent pharyngeal-derived glands, skeletal abnormalities and have complex heart and aortic arch artery defects [25,27]. Pax9 has been shown to functionally interact with Tbx1 in the pharyngeal endoderm for 4th PAA morphogenesis, as double-heterozygous mice develop IAA-B [25].…”

Section: Introductionmentioning

confidence: 99%

“…Mice deficient for Pax9 die perinatally with a cleft palate, absent pharyngeal-derived glands, skeletal abnormalities and have complex heart and aortic arch artery defects [25,27]. Pax9 has been shown to functionally interact with Tbx1 in the pharyngeal endoderm for 4th PAA morphogenesis, as double-heterozygous mice develop IAA-B [25]. Gbx2 has also been implicated in cardiovascular development [28,29] and is normally expressed in all three germ layers of the mouse at the early head fold stage (E7.5) in a domain that extends rostrally from the posterior end of the embryo, encompassing the node, into the prospective hindbrain [30].…”

Section: Introductionmentioning

confidence: 99%

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Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development

Stothard

Mazzotta

Vyas

et al. 2020

JCDD

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The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development.

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Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis

Cited by 28 publications

References 78 publications

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Maternal iron deficiency perturbs embryonic cardiovascular development

Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development

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