Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation

Zhou, Lin; Liu, Jielin; Olson, Patrick; Zhang, Ke; Wynne, Joshua; Xie, Linglin

doi:10.1016/j.yjmcc.2015.05.005

Cited by 42 publications

(56 citation statements)

References 51 publications

(74 reference statements)

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“…Mouse mutants for the important pulmonary gene Wnt2 also lack atrial septa (Tian et al 2010). Finally, crucial mediators of both lung and AS development include members of the Bmp pathway such as Alk3, Bmp4 and Osr1 (Jiao et al 2003;Briggs et al 2013;Zhou et al 2015). Osr1 mutations result in ASDs and lung phenotypes (Wang et al 2005;Xie et al 2012), and knockdown of Osr1 and Osr2 results in lung loss (Rankin et al 2012).…”

Section: Atrial Septum Developmentmentioning

confidence: 99%

Convergent evolutionary reduction of atrial septation in lungless salamanders

Lewis

Howard

2016

Journal of Anatomy

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Nearly two thirds of the approximately 700 species of living salamanders are lungless. These species respire entirely through the skin and buccopharyngeal mucosa. Lung loss dramatically impacts the configuration of the circulatory system but the effects of evolutionary lung loss on cardiac morphology have long been controversial. For example, there is presumably little need for an atrial septum in lungless salamanders due to the absence of pulmonary veins and the presence of a single source of mixed blood flowing into the heart, but whether lungless salamanders possess an atrial septum and whether the sinoatrial aperture is located in the left or right atrium are unresolved; authors have stated opposing claims since the late 1800s. Here, we use micro‐computed tomography (μ‐CT) imaging, gross dissection and histological reconstruction to compare cardiac morphology among lungless plethodontid salamanders (Plethodontidae), salamanders with lungs, and the convergently lungless species Onychodactylus japonicus (Hynobiidae). Plethodontid salamanders have partial atrial septa and incomplete separation of the atrium into left and right halves. Partial septation is also seen in O. japonicus. Hence, lungless salamanders from two lineages convergently evolved similar morphology of the atrial septum. The partial septum in lungless salamanders can make it appear that the sinoatrial aperture is in the left atrium, but this interpretation is incorrect. Outgroup comparisons demonstrate that the aperture is located in a posterodorsal extension of the right atrium into the left side of the heart. Independent evolutionary losses of the atrial septum may have a similar developmental basis. In mammals, the lungs induce formation of the atrial septum by secreting morphogens to neighboring mesenchyme. We hypothesize that the lungs induce atrial septum development in amphibians in a similar fashion to mammals, and that atrial septum reduction in lungless salamanders is a direct result of lunglessness.

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Section: Atrial Septum Developmentmentioning

confidence: 99%

Convergent evolutionary reduction of atrial septation in lungless salamanders

Lewis

Howard

2016

Journal of Anatomy

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“…For example, genetic inducible fate mapping (GIFM) has shown that the entire atrial septum, including the DMP, derives from the SHF (32). Furthermore, the molecular requirement for the Hedgehog (Hh) and BMP signaling pathways and the Tbx5 cardiogenic transcription factor for AV septation reside in the SHF (32)(33)(34)(35)(36)(37)(38). These observations lay the groundwork for investigating the molecular pathways required for atrial septum formation in SHF cardiac progenitor cells.…”

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confidence: 99%

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

Zhou

Liu

Xiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs. Gata4 mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream of Hh components: Gata4 activated a cisregulatory element at Gli1 in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged in Smoothened mutants, and Hh pathway genes were unchanged in Pten mutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominant Gata4 mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.Gata4 | ASDs | Hedgehog signaling | second heart field | cell cycle

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“…2I and I’ vs. 2H and H’, P=1). We next tested if Gata4 is required in the pSHF for OFT alignment in in pSHF-specific Gata4 heterozygous mice by crossing Osr1 CreERT2/+ [46, 47] with Gata4 fl/+ . Similarly, neither Gata4 fl/+ ; Osr1 CreERT2/+ embryos (0/5) nor littermate control Gata4 fl/+ embryos (0/6) demonstrated OFT misalignments at E14.5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Tamoxifen (TM) -induced activation of CreERT2 was accomplished by oral gavage with two doses of 75 mg/kg TM at E7.5 and E8.5 [45, 46]. X-gal staining of embryos was performed as described [45].…”

Section: Methodsmentioning

confidence: 99%

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

Liu

Cheng

Xiang

et al. 2018

Preprint

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32Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), cause 33 outflow tract (OFT) defects in both human and mouse. We investigated the molecular 34 mechanism underlying this requirement. Gata4 happloinsufficiency in mice caused OFT 35 defects including double outlet right ventricle (DORV) and conal ventricular septum 36 defects (VSDs). We found that Gata4 is required within Hedgehog (Hh)-receiving second 37 heart field (SHF) progenitors for normal OFT alignment. Increased Pten-mediated cell-38 cycle transition, rescued atrial septal defects but not OFT defects in Gata4 heterozygotes. 39 SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion in Gata4 40 heterozygote embryos. We find that Hh signaling and Gata4 genetically interact for OFT 41 development. Gata4 and Smo double heterozygotes displayed more severe OFT 42 abnormalities including persistent truncus arteriosus (PTA) whereas restoration of 43 Hedgehog signaling rescued OFT defects in Gata4-mutant mice. In addition, enhanced 44 expression of the Gata6 was observed in the SHF of the Gata4 heterozygotes. These 45 results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling 46 for OFT development. This study indicates that Gata4 potentiation of Hh signaling is a 47 general feature of Gata4-mediated cardiac morphogenesis and provides a model for the 48 molecular basis of CHD caused by dominant transcription factor mutations.49 3 50Gata4 is an important protein that controls the development of the heart. Human who 52 possess a single copy of Gata4 mutation display congenital heart defects (CHD), 53 including the double outlet right ventricle (DORV). DORV is an alignment problem in 54 which both the Aorta and Pulmonary Artery originate from the right ventricle, instead of 55 originating from the left and the right ventricles, respectively. To study how Gata4 56 mutation causes DORV, we used a Gata4 mutant mouse model, which displays DORV. 57We showed that Gata4 is required in the cardiac precursor cells for the normal alignment 58 of the great arteries. Although Gata4 mutation inhibits the rapid increase in number of the 59 cardiac precursor cells, rescuing this defects does not recover the normal alignment of 60 the great arteries. In addition, there is a movement problem of the cardiac precursor cells 61 when migrating toward the great arteries during development. We further showed that a 62 specific molecular signaling, Hh-signaling, is responsible to the Gata4 action in the 63 cardiac precursor cells. Importantly, over-activating the Hh-signaling rescues the DORV 64 in the Gata4 mutant embryos. This study provides an explanation for the ontogeny of 65 CHD. 66 4 67 Introduction 68 Congenital Heart Defects (CHDs) CHDs occurr in approximately 1% of live births [1] 69 and are the most common serious birth defects in humans [2, 3]. Approximately one third 70 of the CHDs involve malformations of the outflow tract (OFT), which leads to significant 71 morbidity and mortality o...

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Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation

Cited by 42 publications

References 51 publications

Convergent evolutionary reduction of atrial septation in lungless salamanders

Convergent evolutionary reduction of atrial septation in lungless salamanders

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

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